Conditions: Multiple Myeloma
Keywords: autologous stem cell transplant HDT/ASCT CTLA-4 PD-L1 peripheral blood mononuclear cells PBMC ASCT
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 6
Healthy volunteers: no

Brief summary:
This was a Phase 1, open-label, multicenter, study of checkpoint inhibitor therapy (tremelimumab ± durvalumab) prior to and following autologous stem cell transplant (ASCT) and high-dose melphalan in subjects with multiple myeloma who were at a high risk for relapse, were eligible for ASCT, and had available cryopreserved stem cells. Primary study objectives were to determine the safety and tolerability of study treatment. Further objectives were to evaluate the clinical efficacy and biologic activity of the regimen.

Detailed description:
Eligible subjects were to be enrolled sequentially into one of 4 treatment cohorts (beginning with Cohort 1) to receive pretreatment with Prevnar-13 on Day -33 ± 2 days, followed by a single dose of tremelimumab (75 mg) administered either alone (Cohorts 1 and 2) or in combination with a single dose of durvalumab (1500 mg; Cohorts 3 and 4) on Day -31 (approximately 21 days prior to steady-state leukopheresis for the collection of autologous peripheral blood lymphocytes \[PBLs\]). Leukopheresis was performed on Days -10 to -3, followed by high dose therapy (HDT) comprising melphalan (200 mg/m\^2) administered intravenously (IV) on Day -2, and ASCT using previously banked hematopoietic stem cells on Day 0. Autologous PBLs were re-infused into subjects on Day +3 following ASCT, with a single dose of tremelimumab (75 mg) administered on the same day. Following HDT/ASCT, treatment was to resume with tremelimumab (75 mg) administered either alone (Cohorts 1 and 2) or in combination with durvalumab (1500 mg; Cohorts 3 and 4) for the first 2 cycles following HDT/ASCT according to the following schedule.

Late post-ASCT treatment:

* Cohort 1: tremelimumab (75 mg) administered alone on Day 100 (±10) and 4 weeks later (Cycles 1 and 2)
* Cohort 3: tremelimumab (75 mg) + durvalumab (1500 mg) administered on Day 100 (±10) and 4 weeks later (Cycles 1 and 2)

Early post-ASCT treatment:

* Cohort 2: tremelimumab (75 mg) administered alone on Days 30 through 40 and Day 100 (±10) (Cycles 1 and 2)
* Cohort 4: tremelimumab (75 mg) + durvalumab (1500 mg) administered on Days 30 through 40 and Day 100 (±10) (Cycles 1 and 2)

For Cycles 3 through 8, durvalumab alone (1500 mg every 4 weeks) was to be administered in all cohorts.

Within each cohort, the second subject did not start treatment until the first subject had completed early engraftment (approximately Day 12 to 18 post-ASCT); therefore, the first subject in each cohort received the first dose of tremelimumab ± durvalumab and was observed for toxicity for approximately 7 weeks prior to enrollment of the second subject.

Protocol-specified dose-limiting toxicities (DLTs) were assessed from the first dose of study treatment up to and including Cycle 2 dosing (Day 128 for Cohorts 1 and 3 or Day 100 for Cohorts 2 and 4). Subjects were not to be treated in a new cohort until all subjects in the previous cohort had completed the DLT evaluation period and ≤ 1 of 6 subjects had experienced DLT.

After enrollment of 6 subjects in Cohort 1, the study was placed on partial clinical hold by the Food and Drug Administration (FDA) due to safety signals observed in other studies investigating pembrolizumab, an anti-programmed cell death-1 (PD-1) antibody, in combination with immunomodulatory agents in subjects with multiple myeloma. As a result, the single subject who was receiving durvalumab during Cycles 3 to 8 discontinued study treatment after Cycle 5; durvalumab was not initiated in the 4 subjects who remained in the study; and no further subjects were enrolled. Upon recommendations from the two Principal Investigators and the study chair, the 4 ongoing subjects, who were in the transplant phase of the study, were permitted to continue post-ASCT tremelimumab treatment after being re-consented under an intermediate expanded access protocol.

Arms:
arm 1: Subjects received Prevnar-13 on Day -33 ± 2 days, tremelimumab (75 mg) on Day -31, leukopheresis on \~Day -10, melphalan (200 mg/m\^2) on Day -2, ASCT on Day 0, and reinfusion of PBLs and tremelimumab (75 mg) on Day 3. "Late" post-ASCT treatment comprised Prevnar-13 on Days 30 and 60, tremelimumab (75 mg) on Day 100 ± 10 days and Day 128 (Cycles 1 and 2), followed by up to 6 cycles of durvalumab (1500 mg) on Day 1 of Cycles 3 through 8. arm 2: Subjects were to receive Prevnar-13 on Day -33 ± 2 days, tremelimumab (75 mg) on Day -31, leukopheresis on \~Day -10, melphalan (200 mg/m\^2) on Day -2, ASCT on Day 0, and reinfusion of PBLs and tremelimumab (75 mg) on Day 3. "Early" post-ASCT treatment comprised Prevnar-13 on Days 30 and 60, tremelimumab (75 mg) on Days 30 through 40 and Day 100 ± 10 days (Cycles 1 and 2), followed by up to 6 cycles of durvalumab (1500 mg) on Day 1 of Cycles 3 through 8. arm 3: Subjects were to receive Prevnar-13 on Day -33 ± 2 days, tremelimumab (75 mg) + durvalumab (1500 mg) on Day -31, leukopheresis on \~Day -10, melphalan (200 mg/m\^2) on Day -2, ASCT on Day 0, and reinfusion of PBLs and tremelimumab (75 mg) on Day 3. "Late" post-ASCT treatment comprised Prevnar-13 on Days 30 and 60, tremelimumab (75 mg) + durvalumab (1500 mg) on Day 100 ± 10 days and Day 128 (Cycles 1 and 2), followed by up to 6 cycles of durvalumab (1500 mg) on Day 1 of Cycles 3 through 8. arm 4: Subjects were to receive Prevnar-13 on Day -33 ± 2 days, tremelimumab (75 mg) + durvalumab (1500 mg) on Day -31, leukopheresis on \~Day -10, melphalan (200 mg/m\^2) on Day -2, ASCT on Day 0, and reinfusion of PBLs and tremelimumab (75 mg) on Day 3. "Early" post-ASCT treatment comprised Prevnar-13 on Days 30 and 60, tremelimumab (75 mg) + durvalumab (1500 mg) on Days 30 through 40 and Day 100 ± 10 days (Cycles 1 and 2), followed by up to 6 cycles of durvalumab (1500 mg) on Day 1 of Cycles 3 through 8.

Interventions: intervention 1: Tremelimumab intervention 2: Durvalumab intervention 3: Prevnar-13 intervention 4: Melphalan
Intervention descriptions: intervention 1: Tremelimumab was administered as an intravenous (IV) infusion over 60 ± 5 minutes at a fixed dose of 75 mg, regardless of weight. intervention 2: Durvalumab was administered as an IV infusion over 60 ± 5 minutes at a fixed dose of 1500 mg for subjects weighing \> 30 kg. If a subject's body weight dropped to ≤ 30 kg on study, the subject was dosed at 600 mg for as long as the body weight remained ≤ 30 kg.

When applicable, the durvalumab infusion was to start at least 60 minutes after the end of the tremelimumab infusion. intervention 3: Prevnar-13 was administered as an intramuscular injection. The Prevnar-13 dose and the tremelimumab dose were to be separated by a minimum of 48 hours. intervention 4: Melphalan was administered as an IV infusion according to institutional standard of care and local prescribing information.

Protocol document:
Prot_SAP_000.pdf: 
 
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Study Protocol 
LUD2014-010 
US-IND# 129021 
NCT02716805 
Amendment 3 
Final 
28-MAR-2017 
 
Protocol Title 
A Phase 1 Study to Assess Safety and Tolerability of Tremelimumab and Durvalumab, 
Administered with High Dose Chemotherapy and Autologous Stem Cell Transplant 
(HDT/ASCT) 
  
Objectives and Synopsis 
This is an open-label, multicenter, Phase 1 study of checkpoint therapy, tremelimumab 
(MEDI1123) and durvalumab (MEDI4736), administered to subjects with multiple myeloma who 
are at high risk for relapse.  Four cohorts will be included in the study. The cohorts are based on 
subjects receiving tremelimumab 75 mg alone (Cohorts 1 and 2) or durvalumab 1500 mg + 
tremelimumab 75 mg (Cohorts 3 and 4) prior to and for 2 cycles post autologous stem cell 
transplant (ASCT) as well as 2 different schedules of post ASCT therapy: Late (Cohorts 1 and 3) 
and Early (Cohorts 2 and 4) as described below.  
Subjects will receive a single dose of tremelimumab 75 mg alone (Cohorts 1 and 2) or a single 
dose of durvalumab 1500 mg + tremelimumab 75 mg (Cohorts 3 and 4) at 21 days prior to 
steady state leukopheresis for the collection of autologous peripheral blood lymphocytes (PBLs).  
Leukopheresis will be followed by high dose therapy (HDT, melphalan 200 mg/m2 IV) and ASCT 
using previously banked hematopoietic stem cells.  Autologous PBLs will be infused into subjects 
on Day +3 following HDT/ASCT, and a single dose of tremelimumab 75 mg will be administered 
on the same day.  Following HDT/ASCT, treatment will resume with tremelimumab 75 mg alone 
(Cohorts 1 and 2) or durvalumab 1500 mg + tremelimumab 75 mg (Cohorts 3 and 4) for the first 
2 cycles post HDT/ASCT according to the following schedule: 
• 
Late Post ASCT Treatment: 
o 
Cohort 1 - tremelimumab 75 mg alone on Day 100 (±10) and 4 weeks later (Cycles 1 and 2) 
o 
Cohort 3 –- tremelimumab 75 mg + durvalumab 1500 mg on Day 100 (±10) and 4 weeks later 
(Cycles 1 and 2) 
• 
Early Post ASCT Treatment: 
o 
Cohort 2- tremelimumab 75 mg alone on Day 30-40 and Day 100 (±10) (Cycles 1 and 2) 
o 
Cohort 4 – tremelimumab 75 mg + durvalumab 1500 mg on Day 30-40 and Day 100 (±10) 
(Cycles 1 and 2) 
For Cycles 3 to 8, durvalumab alone (1500 mg every 4 weeks) will continue to be administered 
for all cohorts.   
Cohort enrollment will be sequential so that Cohort 1 will be treated first, followed by a 
safety review before each subsequent cohort will be opened. 
Primary 
Objectives 
[Endpoints] 
Safety and Tolerability of durvalumab/tremelimumab [DLTs, AEs 
according to CTCAE version 4.03]. 
Secondary 
Objectives  
[Endpoints] 
Clinical efficacy [response by IMWG criteria, minimal residual disease 
assessment, one-year PFS and OS, 100-day ASCT related mortality]. 


 
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Sponsor: Ludwig Institute for Cancer Research 
 
 
 
 
 
 
 
 
Sponsor representative Signature and Date 
Study Chair:  Alexander M. Lesokhin, MD, 
Memorial Sloan-Kettering Cancer Center 
 
 
 
 
 
 
 
Study Chair Signature and Date 
 
Confidentiality Statement 
The confidential and proprietary information in this document is owned by the Ludwig Institute for Cancer Research and provided to 
you as an Investigator, potential Investigator, or consultant, for review by you, your staff, and applicable institutional review 
board(s).  The information cannot be used, or divulged to any third party or published without the written consent of the Ludwig 
Institute for Cancer Research, except to the extent necessary to obtain informed consent from those persons to whom study 
medication may be administered.  Any misappropriation of this information is prohibited by law. 
Exploratory 
Objective 
[Endpoints] 
Biological Activity [Gene expression, mutation analysis, and protein 
expression of immune regulation markers of tumor cell populations. 
Effects of PBL and durvalumab / tremelimumab combination on 
immune reconstitution, T and B cell receptor diversity, and immune 
responses to Prevnar-13 and myeloma antigens]. 
DLT=Dose-limiting Toxicity; AE=adverse event; PFS=Progression-free Survival; OS=Overall Survival; 
CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; IMWG=International 
Myeloma Working Group; ASCT=Autologous stem cell transplant; PBL=Peripheral blood lymphocytes 


 
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Table of Contents 
 
1 
Background ...................................................................................................................................... 7 
1.1 
Multiple Myeloma ................................................................................................................... 7 
1.2 
CTLA-4 ...................................................................................................................................... 7 
1.3 
PD-1 and PD-L1 ........................................................................................................................ 8 
1.4 
Tremelimumab (MEDI1123) - CTLA-4 blocking antibody ........................................................ 9 
1.5 
Durvalumab (MEDI4736) - PD-L1 Blocking Antibody ............................................................ 10 
1.6 
Peripheral Blood Mononuclear Cell Reconstitution in Autologous Stem Cell Transplant for 
Multiple Myeloma............................................................................................................................. 11 
2 
Study Rationale ..............................................................................................................................12 
3 
Experimental Plan ..........................................................................................................................14 
3.1 
Study Design .......................................................................................................................... 14 
3.1.1 
Study Phase ....................................................................................................................14 
3.1.2 
Enrollment/Randomization ............................................................................................14 
3.1.3 
Blinding/Unblinding ........................................................................................................14 
3.1.4 
Subject Population .........................................................................................................14 
3.1.5 
No. of Sites/Subjects ......................................................................................................14 
3.1.6 
Sample Size Considerations ............................................................................................14 
3.1.7 
Treatment Cohorts and Treatment Schema ..................................................................15 
3.1.8 
Dosing Adjustments, Delays and Discontinuations ........................................................19 
3.1.9 
Dose Limiting Toxicity (DLT) and MTD/RCD ...................................................................19 
3.1.10 
Subject Withdrawal from Treatment or from Study ......................................................20 
3.1.11 
Subject Evaluability and Replacement ...........................................................................21 
3.1.12 
Optional Study Treatment Extension .............................................................................21 
3.1.13 
Interim Analysis ..............................................................................................................21 
3.1.14 
Safety Monitoring and Study Stopping Rules .................................................................21 
3.1.15 
Duration of Study ...........................................................................................................22 
3.1.16 
On Study and Post Study Follow-up ...............................................................................22 
 
End of Study Visit ....................................................................................................23 
3.2 
Study Flowchart ..................................................................................................................... 24 
4 
Study Objectives and Endpoints ....................................................................................................28 
4.1 
Safety and Tolerability ........................................................................................................... 28 
4.1.1 
Endpoints and Assessment Methods .............................................................................28 
4.1.2 
Subject Evaluation and Statistics ....................................................................................28 
4.2 
Clinical Efficacy ...................................................................................................................... 29 
4.2.1 
Endpoints and Assessment Methods .............................................................................29 
 
Multiple Myeloma Response Assessment by IMWG Consensus Criteria...............29 
 
100-Day Post Autologous Stem Cell Transplant Mortality Rate .............................29 
 
Minimal Residual Disease Assessment ...................................................................29 
 
Progression-Free Survival (PFS) ..............................................................................29 
 
Overall Survival (OS) ...............................................................................................30 


 
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4.2.2 
Subject Evaluation and Statistics ....................................................................................30 
4.3 
Biological Activity .................................................................................................................. 30 
4.3.1 
Endpoints and Assessment Methods .............................................................................30 
 
Circulating Soluble Factors (Cytokine Profiling) .....................................................30 
 
Pneumococcal Serology ..........................................................................................30 
 
PBMC/BMMC Banking ............................................................................................30 
 
Flow cytometry for Immune Reconstitution (Immune monitoring) ......................31 
 
Bone Marrow Biopsies ...........................................................................................31 
 
Additional translational and exploratory studies ...................................................31 
 
Genomic Profiling ...................................................................................................32 
4.3.2 
Subject Evaluation and Statistics ....................................................................................32 
5 
Subject Eligibility ............................................................................................................................33 
5.1 
Inclusion Criteria .................................................................................................................... 33 
5.2 
Exclusion Criteria ................................................................................................................... 34 
5.3 
Restrictions on Concomitant Therapies ................................................................................ 37 
5.3.1 
Non-Permitted Concomitant Therapies .........................................................................37 
5.3.2 
Permitted Concomitant Therapies .................................................................................37 
6 
Study Drugs Preparation and Administration ................................................................................38 
6.1 
Durvalumab (MEDI4736) ....................................................................................................... 38 
6.1.1 
Study Drug Information ..................................................................................................38 
6.1.2 
Durvalumab Investigational Product Inspection ............................................................38 
6.1.3 
Durvalumab Preparation ................................................................................................38 
6.1.4 
Durvalumab Administration ...........................................................................................39 
6.2 
Tremelimumab ...................................................................................................................... 40 
6.2.1 
Study Drug Information ..................................................................................................40 
6.2.2 
Tremelimumab Investigational Product Inspection .......................................................40 
6.2.3 
Tremelimumab Preparation ...........................................................................................40 
6.2.4 
Tremelimumab Administration ......................................................................................41 
6.3 
Estimated Study Drug Requirements .................................................................................... 42 
6.4 
Drug Overdose Management ................................................................................................ 42 
6.5 
Monitoring of Tremelimumab and Durvalumab Dose Administration ................................. 42 
7 
Administrative, Legal and Ethical Requirements ...........................................................................44 
7.1 
Documentation and Reporting of Adverse Events ................................................................ 44 
7.1.1 
Definitions ......................................................................................................................44 
7.1.2 
Additional Expedited Reporting Requirements for this Study .......................................45 
 
Pregnancy ...............................................................................................................45 
 
Overdose ................................................................................................................46 
 
Hepatic Function Abnormality ................................................................................46 
7.1.3 
Severity of an Adverse Event ..........................................................................................46 
7.1.4 
Relationship of Adverse Events to Study Drug ...............................................................46 
7.1.5 
General Reporting Requirements ...................................................................................47 
7.1.6 
Expedited Serious Adverse Event (SAE) Reporting Requirements .................................47 
7.1.7 
Serious Adverse Event (SAE) Follow-up Requirements ..................................................48 


 
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7.1.8 
Adverse Events of Special Interest (AESIs) .....................................................................48 
7.2 
Administrative Sponsor Requirements ................................................................................. 51 
7.2.1 
Study Master Files ..........................................................................................................51 
7.2.2 
Case Report Form Data Collection .................................................................................51 
7.2.3 
Language ........................................................................................................................51 
7.2.4 
Monitoring ......................................................................................................................51 
7.2.5 
Protocol Amendments....................................................................................................52 
7.2.6 
Premature Subject Withdrawal from Treatment or from Study ....................................52 
7.2.7 
Early Trial Termination ...................................................................................................52 
7.2.8 
Study Drug Shipments and Accountability .....................................................................52 
7.3 
Regulatory, Legal and Ethical Requirements ......................................................................... 53 
7.3.1 
Good Clinical Practice (GCP), Laws and Regulations ......................................................53 
7.3.2 
Informed Consent ...........................................................................................................53 
7.3.3 
Institutional Review Board .............................................................................................53 
7.3.4 
Subject Confidentiality ...................................................................................................54 
8 
Appendices ....................................................................................................................................55 
8.1 
Protocol Version History........................................................................................................ 55 
8.2 
Participating Study Sites, Investigators and Staff, Laboratories, and Sponsor Information . 62 
8.3 
Dose Adjustments and Delays for Durvalumab and Tremelimumab .................................... 63 
8.3.1 
Durvalumab and Tremelimumab Dose Modification Due to Toxicity ............................63 
8.3.2 
Durvalumab and Tremelimumab Dose Modification Not Due to Treatment-related 
Toxicities ........................................................................................................................................65 
8.4 
International Myeloma Working Group (IMWG) Criteria for Multiple Myeloma ................. 67 
8.5 
Laboratory Procedures .......................................................................................................... 70 
8.6 
ECOG Performance Status ..................................................................................................... 71 
8.7 
List of Abbreviations .............................................................................................................. 72 
9 
References .....................................................................................................................................74 
 
 
 


 
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Table of Figures  
Figure 1: Treatment Schema for Cohort 1............................................................................................. 17 
Figure 2: Treatment Schema for Cohort 2............................................................................................. 18 
Figure 3: Treatment Schema for Cohort 3............................................................................................. 18 
Figure 4: Treatment Schema for Cohort 4............................................................................................. 19 
 
 


 
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1 
Background  
1.1 Multiple Myeloma 
Multiple myeloma (MM) is a malignancy of plasma cells and is the second most common hematologic 
malignancy.(1)  It is characterized by clonal expansion of malignant plasma cells and manifests 
symptoms encapsulated by the acronym CRAB; hyperCalcemia, Renal impairment, Anemia, and lytic 
Bone disease.  The pathogenesis of MM is complex.  Several studies have shown that myeloma cells 
acquire certain genetic changes that allow for uncontrolled growth, migration, and protection from 
apoptosis.(2-4)  The bone marrow microenvironment also appears to play a critical role in the 
development and persistence of the disease, with interactions with osteoclasts, stromal cells, and 
cells of the immune system mediated by cell surface and soluble mediators.(5, 6) 
Multiple myeloma represents 1% of all cancers in the United States, with approximately 27,000 new 
cases diagnosed each year with an incidence of 6.3 cases per 100,000 and 11,000 deaths yearly.(7)  
There are approximately 90,000 people living with MM in the United States.  Worldwide, there are 
103,000 new cases and 72,000 deaths from myeloma each year. The median age at diagnosis is 70, 
and because of anticipated changes in demographics, by the year 2020, it is predicted that there will 
be 140,000 new cases each year with 100,000 deaths (8).  The incidence of MM in Europe is 6.0 cases 
per 100,000 per year with a median age at diagnosis between 63 and 70 years; the mortality is 4.1 
cases per 100,000 per year.(9)  Currently approved regimens commonly used for MM include 
combinations of the proteasome inhibitors bortezomib and/or immune modulatory drugs (IMiDs) 
including thalidomide or lenalidomide with corticosteroids for induction, high dose chemotherapy 
and autologous stem cell transplant (ASCT) for consolidation therapy, and combinations of novel 
agents with conventional cytotoxic chemotherapy for relapsed disease.(1)   
Numerous clinical trials have demonstrated that high dose chemotherapy and ASCT confers 
improved disease-free and overall survival compared to conventional dose chemotherapy.(10-13)  
The survival benefit is most evident in subjects 65 years of age or younger with good performances 
status and few or no significant co-morbidities.  In general, the conditioning regimen for this 
procedure consists of melphalan (L-PAM) as a single or split intravenous dose of 200 mg/m2. 
Autologous stem cell transplant is now accepted in the standard-of-care management of newly 
diagnosed MM patients. Several studies have shown that a second ASCT is an effective salvage 
therapy in subjects with relapsed disease.(14-16)  In general, second transplants feature conditioning 
regimens consisting of a reduced dose of melphalan (100-140 mg/m2) alone or in combination with 
other alkylating agents such as BCNU (carmustine) in order to reduce morbidity associated with the 
procedure.  Although salvage ASCT has not been shown to improve overall survival, the response 
rates are high, and this strategy is commonly used to restore bone marrow reserve in patients in 
anticipation of further therapy.   
Despite these advances, relapse is inevitable and the majority of patients will eventually succumb to 
multiple myeloma.  
1.2 CTLA-4 
Human cytotoxic T lymphocyte-associated antigen 4 (CTLA-4; CD152) is a cell surface receptor that is 
expressed primarily on activated T cells and acts to inhibit their activation.  The canonical 
coinhibitory receptor was cloned in 1987 (17); however, it took several years to appreciate the 


 
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unique role of CTLA-4 in attenuating T cell activation.(18-20)  Human cytotoxic T lymphocyte-
associated antigen 4 engagement on activated T cells inhibits cytokine synthesis and restricts cell 
proliferation.(19-23)  Characterization of CTLA-4 -/- knockout mice established a critical negative 
regulatory function for CTLA-4 in vivo.  These mice develop a profound, hyperproliferative 
lymphocyte expansion, which is lethal within 3 weeks after birth.(24-27)  On a cellular level, CTLA-4-
mediated inhibition of T cell activation relies on several overlapping mechanisms.  First, CTLA-4 
competes with CD28 for interaction with the ligands B7-1 and B7-2.  Secondly, CTLA-4 engagement 
impacts multiple intracellular pathways.  Inhibitory signaling is thought to be mediated by (1) 
association with intracellular phosphatases like Src homology 2 (SH2) domain-containing 
phosphatase-1 (SHP-1), SHP-2, and protein phosphatase 2A (PP2A), (2) blockade of lipid-raft 
expression, and (3) disruption of microcluster formation (reviewed by Rudd et al. 2009 (27)).  
1.3 PD-1 and PD-L1 
Programmed death-1 (PD-1, cluster of differentiation [CD] 279) is a member of the immunoglobulin 
superfamily (IGSF) of molecules involved in regulation of T cell activation.  Programmed death-1 
acquired its name when it was identified in 1992 as a gene upregulated in T cell hybridoma 
undergoing cell death.(28)  The structure of PD-1 is composed of one IGSF domain, a transmembrane 
domain, and an intracellular domain containing an immunoreceptor tyrosine-based inhibitory motif 
(ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM).(29-32)  Programmed Death-1 has 
two binding partners: PD-ligand 1 ([PD-L1] B7-H1, CD274) and PD-ligand 2 ([PD-L2] B7-DC, CD273), 
distant relatives of the B7-1 and B7-2 molecules.  Discovered in 1999, PD-L1 is expressed quite 
broadly on both hematopoietic and non-hematopoietic lineages.(32, 33)  It is found on T cell, B cells, 
macrophages, natural killer (NK) cells, dendritic cells (DCs), and mast cells.  It has also been described 
on peripheral tissues including cardiac endothelium, lung, small intestine, keratinocytes, islet cells of 
the pancreas, and syncytiotrophoblasts in the placenta as well as a variety of tumor cell types.(18, 
34-45)  Programmed death-L1 is constitutively expressed on many hematopoietic cells, but may be 
upregulated in hematopoietic and non-hematopoietic cells.  Regulation of PD-L1 is mediated, in part, 
by type I and type II interferons.  Programmed death-ligand 2 was identified in 2001.(46, 47)  Its 
expression is far more restricted and is confined to hematopoietic cells.  
Engagement of PD-1 on T cells inhibits activation with downstream effects on cytokine production, 
proliferation, cell survival, and transcription factors associated with effector T cell function.(33, 48-
52)  Inhibitory signaling by PD-1 is thought to depend upon the cytosolic ITSM domain, which 
associates with phosphatases SHP-1 and SHP-2.(53, 54)  While CTLA-4 and PD-1 are both inhibitory 
receptors, they fulfill distinct roles and mediate their effects through distinct mechanisms.(55)  For 
example, PD-1 inhibits activation of the serine threonine kinase Akt via its effect on the 
phosphoinositide 3-kinase (PI3K) pathway, whereas CTLA-4 inhibits Akt in a PI3K independent 
manner.(49, 53, 56)  Studies of PD-1 -/- knockout and PD-L -/- knockout mice support a unique role 
for PD-1: PD-L interaction in mediating peripheral tolerance and preventing autoimmunity.(37)  The 
phenotype of the PD-1-/- knockout mouse depends upon the genetic background, but manifestations 
of spontaneous autoimmunity have been reported, including dilated cardiomyopathy and 
glomerulonephritis.(57, 58) 
Programmed death-L1 and PD-L2 are expressed on many human tumors including urothelial, ovarian, 
breast, cervical, colon, pancreatic, gastric cancers as well as melanoma glioblastoma, and non-small 
cell lung cancer (NSCLC).(18, 34, 35, 38, 39, 43, 59-65)  In addition, PD-L1 and PD-L2 have been 


 
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detected on several hematologic malignancies including: Hodgkin lymphoma, primary mediastinal B 
cell lymphoma, angioimmunoblastic T-cell lymphoma, multiple myeloma, acute myeloid leukemia 
chronic lymphocytic leukemia, and adult T-cell leukemia/lymphoma.(45, 66-69)  Expression of PD-L 
has been correlated with prognosis in many of these malignancies, fueling the hypothesis that PD-L 
expression is a mechanism for tumor immune evasion.(60, 63, 64, 70)  Additionally, PD-1 is highly 
expressed on lymphocytes infiltrating human tumors and circulating tumor-specific T cells, a 
phenotype correlated with impaired T cell function.(71-74)  Together, these findings suggest that 
interrupting PD-1: PD-L interaction could be an effective anti-cancer therapy. 
PD-L1 is part of a complex system of receptors and ligands that are involved in controlling T-cell 
activation.  PD-L1 acts at multiple sites in the body to help regulate normal immune responses by 
delivering inhibitory signals to T cells through the PD-1 and CD80 receptors. 
1.4 Tremelimumab (MEDI1123) - CTLA-4 blocking antibody  
Tremelimumab is briefly described in this section. Refer to the current Investigator Brochure (IB) for 
complete and current information. 
Tremelimumab is a human immunoglobulin (Ig) G2 monoclonal antibody (mAb) being investigated as 
a cancer immunotherapeutic agent.  Tremelimumab is specific for human cytotoxic T lymphocyte-
associated antigen 4 (CTLA-4; CD152), a cell surface receptor that is expressed primarily on activated 
T cells and acts to inhibit their activation. 
As of the data cutoff date of 12Nov2014 (for all studies except D4190C00006 that has a cutoff 
date of 04Dec2014), 22 sponsored clinical studies have been conducted as part of the 
tremelimumab clinical development program. Of these studies, 13 have been completed and 9 
are ongoing. Tremelimumab has been administered as monotherapy to 973 subjects 
participating in 10 of the 22 clinical studies, 2 of which are ongoing. An additional 497 subjects 
have received tremelimumab or placebo in the ongoing double-blinded, Phase 2b mesothelioma 
study, D4880C00003 (DETERMINE; data remain blinded). Tremelimumab in combination with 
other anticancer agents has been administered to 208 subjects with a variety of tumor types in 
12 of the 22 clinical studies, 7 of which are ongoing. 
In clinical subjects, tremelimumab exhibits linear (dose-proportional) PK following intravenous 
(IV) infusion. 
Across the clinical development program for tremelimumab, a pattern of efficacy has emerged, 
also observed for the related anti-CTLA-4 antibody, ipilimumab, which appears to be consistent 
across tumor types for this mechanism of action. Response rates to anti-CTLA-4 antibodies are 
generally low, approximately 10%. However, in subjects who respond, the responses are 
generally durable, lasting several months even in subjects with aggressive tumors such as 
refractory metastatic melanoma. Some subjects may have what is perceived to be progression of 
their disease in advance of developing disease stabilization or a tumor response. Overall, the 
impact on conventionally-defined progression-free survival (PFS) can be small; however, the 
durable response or stable disease seen in a proportion of subjects can lead to significant 
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The profile of adverse events (AEs) and the spectrum of event severity have remained stable 
across the tremelimumab clinical program and are consistent with the pharmacology of the 
target. To date, no tumor type or stage appears to be associated with unique AEs (except for 
vitiligo that appears to be confined to subjects with melanoma).  
As of the data cutoff date of 12Nov2014 (for all studies except D4190C00006 that has a cutoff 
date of 04Dec2014), AEs (all grades, regardless of causality) reported in > 10% of subjects in the 
completed and rollover tremelimumab monotherapy studies (N = 973, integrated data) were 
diarrhea (45.3%), fatigue (37.5%), nausea (32.5%), rash (28.8%), pruritus (27.3%), decreased 
appetite (22.8%), vomiting (22.5%), pyrexia (15.3%), cough (15.0%), constipation (14.4%), 
abdominal pain (13.9%), headache (13.8%), dyspnea (12.4%), and decreased weight (10.2%). 
Based on integrated data from completed studies of tremelimumab in combination with other 
agents (N = 116), AEs (all grades, regardless of causality) reported in > 15% of subjects were 
diarrhea (54.3%); nausea (40.5%); fatigue (38.8%); rash (35.3%); pruritus, decreased appetite 
(30.2% each); vomiting (27.6%); pyrexia (26.7%); influenza like illness (20.7%); arthralgia (19.8%); 
constipation (19.0%); thrombocytopenia, injection site reaction (18.1% each); and increased 
aspartate aminotransferase (15.5%). Most of these events occurred at a higher rate with 
tremelimumab plus sunitinib than with other combinations. The events of diarrhea, rash, and 
pruritus are considered identified risks of tremelimumab. Acute renal failure was reported in 
subjects who received the combination of tremelimumab and sunitinib; however, acute renal 
failure has not been an expected AE for single-agent tremelimumab. The incidence and/or 
severity of many of the AEs observed following administration of tremelimumab can be reduced 
by following current guidelines for the management of immune-related toxicities. 
1.5 Durvalumab (MEDI4736) - PD-L1 Blocking Antibody  
Durvalumab is briefly described in this section. Refer to the current Investigator Brochure (IB) for 
complete and current information. 
Durvalumab is a human mAb of the immunoglobulin G1 kappa (IgG1κ) subclass that inhibits binding 
of PD-L1 (B7 homolog 1 [B7-H1], CD274) to PD-1 (CD279) and CD80 (B7-1). Durvalumab is composed 
of 2 identical heavy chains and 2 identical light chains, with an overall molecular weight of 
approximately 149 kDa. Durvalumab contains a triple mutation in the constant domain of the 
immunoglobulin (Ig) G1 heavy chain that reduces binding to complement protein C1q and the 
fragment crystallizable gamma (Fcγ) receptors involved in triggering effector function. 
As of the data cutoff dates in the IB (15Apr2015 to 12Jul2015), a total of 1,883 subjects have been 
enrolled and treated in 30 ongoing durvalumab clinical studies, including 20 sponsored 
(6 monotherapy and 14 combination therapy) and 10 collaborative studies. Of the 1,883 subjects, 
1,279 received durvalumab monotherapy, 440 received durvalumab in combination with 
tremelimumab or other anticancer agents, 14 received other agents (1 gefitinib, 13 MEDI6383), and 
150 have been treated with blinded investigational product. No studies have been completed or 
terminated prematurely due to toxicity. 
The safety profile of durvalumab as monotherapy and combined with other anticancer agents was 
consistent with the pharmacology of the target and other agents in the immune checkpoint inhibitor 
class. No tumor types appeared to be associated with unique AEs. Immune-related AEs (irAEs), which 


 
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are important risks of immune checkpoint inhibitors, have been observed with durvalumab and 
include colitis, pneumonitis, hepatitis/hepatotoxicity, neuropathy / neuromuscular toxicity, 
endocrinopathy, dermatitis, and nephritis. In addition, pancreatitis is an important potential risk 
particularly with durvalumab and tremelimumab combination therapy. These events are manageable 
by available/established treatment guidelines as described in the study protocols.  
Partial efficacy data are available for 2 monotherapy studies (CD-ON-MEDI4736-1108 and 
D4190C00007) and 2 combination therapy studies (CD-ON-MEDI4736-1161 and D4190C00006). 
Clinical activity has been observed across the 4 studies. 
1.6 Peripheral Blood Mononuclear Cell Reconstitution in Autologous Stem 
Cell Transplant for Multiple Myeloma 
Immune competence is a significant factor for consideration of immunologic therapy in the setting of 
ASCT. Subjects experience significant lymphopenia in the post ASCT period and have demonstrated 
poor or absent responses to infectious disease vaccines up to one year after ASCT.(75, 76)  However, 
clinical studies demonstrate that immune competence can be restored by reconstitution of 
peripheral blood lymphocytes harvested prior to the myeloablative conditioning regimen of ASCT. In 
this strategy, peripheral blood mononuclear cells (PBMCs), including lymphocytes and NK cells, are 
harvested by leukopheresis prior to conditioning chemotherapy. In some studies, peripheral blood 
lymphocytes (PBLs) are then expanded ex vivo by co-incubation with recombinant human IL-2 and 
paramagnetic beads conjugated to activating monoclonal antibodies directed against the T cell 
activation receptors CD3 and CD28, and these PBL are re-infused into subjects after conditioning 
chemotherapy and stem cell rescue.(77, 78)  Rapoport and colleagues demonstrated that this 
approach could successfully induce robust humoral and cellular immune responses to infectious 
disease or tumor antigen vaccines in MM subjects undergoing ASCT.(77, 78)  The ex vivo activation 
step is not required for restoration of immune responsiveness. Reinfusion of unmanipulated PBMCs 
harvested prior to conditioning chemotherapy resulted in robust humoral immune responses to a 
recombinant MAGE-A3 vaccine administered to subjects undergoing ASCT for MM.(79)  Ex vivo 
activated PBL reinfusion was associated in some cases with hyperleukocytosis and grade 1-3 GI and 
skin AEs that were indistinguishable from graft-versus-host disease.(80) In contrast, reconstitution of 
unmanipulated PBMC post-transplant was not reported to have significant adverse effects in the 
MAGE-A3 vaccine trial. 
 
 
 


 
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2 
Study Rationale 
Despite advances in MM, relapse in these patients is inevitable and the majority of patients will 
eventually succumb to the disease.  The success of CTLA-4 and PD-1 directed immunotherapy in solid 
tumors has fueled clinical investigation of checkpoint blockade in hematologic malignancies. The 
mechanisms of action for CTLA-4 and PD-1 are non-redundant with respect to T-cell function, 
suggesting that targeting both pathways may have additive or synergistic activity.(81)  Also, 
preclinical data in mouse models of transplantable solid tumors supports the superior anti-tumor 
activity of combination therapy over monotherapy.(82, 83)  Based upon these observations, 
combination therapy may generate superior anti-tumor activity (compared to monotherapy), which 
may translate into high rates of response in tumors known to respond to immunotherapies, or 
increased likelihood of activity in tumors that have previously not shown high levels of 
responsiveness to immunotherapy.   
Tremelimumab has a well characterized toxicity profile and evidence for clinical activity, as outlined 
above.  The safety, tolerability, pharmacokinetics and antitumor activity of durvalumab alone and in 
combination with tremelimumab have also been characterized in ongoing studies.  Although most of 
the data for these 2 drugs were generated from solid tumor studies, data from other checkpoint 
inhibitors (ipilimumab and nivolumab) indicate the toxicity is similar for hematologic cancers and no 
unexpected toxicities were seen in patients with hematologic cancers.  There are sufficient data to 
identify doses to be used in this study. 
The combination dose selection of 1 mg/kg Q4W for tremelimumab and 20 mg/kg Q4W for 
durvalumab was based on the identification of an optimal dose of durvalumab that would “yield 
sustained target suppression, optimize synergy of the combination, while maintaining the balance of 
safety in combination with tremelimumab.” This is consistent with the dosing regimen to be 
evaluated in the MedImmune program going forward. 
The fixed dosing is based on information from MedImmune, which indicates that the dose and 
schedule of 1500 mg durvalumab Q4W and 75 mg tremelimumab Q4W was selected based on PK 
models as described below.   
Using population PK models, simulations indicated that both body weight-based and fixed dosing 
regimens of durvalumab and tremelimumab yield similar median steady state PK concentrations with 
slightly less between-subject variability with fixed dosing regimens.  A fixed dosing approach is 
preferred by the prescribing community due to ease of use and reduced dosing errors. Given 
expectation of similar PK exposure and variability, MedImmune considers it feasible to switch to 
fixed dosing regimens. Based on an average body weight of 75 kg, a fixed dose of 750 mg Q2W 
durvalumab is equivalent to 10 mg/kg Q2W, 1500 mg Q4W durvalumab is equivalent to 20 mg/kg 
Q4W, and 75 mg Q4W tremelimumab is equivalent to 1 mg/kg Q4W. 
Fixed dosing for durvalumab is recommended only for subjects with > 30kg body weight due to 
endotoxin exposure.  Subjects with a body weight ≤ 30 kg are not eligible for enrollment in the 
current study.  If a subject’s body weight drops to ≤ 30 kg while on the study, the subject will be 
dosed according to the details provided in Section 6.1.   
The goal of this study is to build on prior work using ASCT as a novel area for the application of 
cellular and immune based therapies.(77, 78, 84, 85)  Much of this work has been performed in 


 
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subjects with multiple myeloma.  In more recent studies, immune efficacy of autologous lymphocyte 
infusion early post ASCT was shown without a need for ex vivo manipulation.  Administering 
checkpoint blockade in this setting seeks to investigate if an autologous lymphocyte product 
transferred into a favorable milieu for homeostatic reconstitution can effectively break immune 
tolerance against tumor-associated antigens that are either mutated or ectopically expressed.  The 
safety and efficacy profile of leukopheresis followed by HDT/ASCT and lymphocyte infusions has 
been studied and is well characterized.  This will make it easier to identify any safety signals related 
to the durvalumab / tremelimumab combination therapy.  Compelling data regarding the 
combination of PD-1/PD-L1 and CTLA-4 blockade and their synergistic effects support evaluating the 
combination of the 2 drugs at a level at or below the maximum tolerated dose (MTD) established by 
ongoing solid tumor durvalumab / tremelimumab combination studies.   
The cohorts proposed in the study are to evaluate the impact of checkpoint inhibitor therapy (using 1 
or 2 checkpoint inhibitors) at different time points in the peri-transplant period.  In a retrospective 
analysis, Rueff et al. demonstrated that CD8 T cell and NK cells achieved healthy donor levels at 
1 month post ASCT.(86)  This supports the inclusion of the early treatment cohorts at Day 30 post 
ASCT.  The stable recovery of B, T and NK cell compartments at approximately Day 100 justifies the 
incorporation of the cohorts at Day 100 post ASCT.(77) 
 


 
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3 
Experimental Plan 
3.1 Study Design 
This is an open-label, multicenter, Phase 1 study of checkpoint therapy, tremelimumab 75 mg and 
durvalumab 1500 mg, administered to subjects with multiple myeloma who are at high risk for 
relapse.  Four cohorts will be included in the study. The cohorts are based on subjects receiving 
tremelimumab 75 mg alone (Cohorts 1 and 2) or durvalumab 1500 mg + tremelimumab 75 mg 
(Cohorts 3 and 4) prior to and for 2 cycles post autologous stem cell transplant (ASCT) as well as 2 
different schedules of post ASCT therapy: Late (Cohorts 1 and 3) and Early (Cohorts 2 and 4) as 
described below. 
3.1.1 Study Phase 
Phase 1 
3.1.2 Enrollment/Randomization 
This is a multicenter study with central subject registration.   
Cohort enrollment will be sequential so that Cohort 1 will be treated first, followed by a safety review 
before each subsequent cohort will be opened. Subjects will not be treated as part of a new cohort 
until all subjects in the previous cohort have completed the DLT observation period, and there was 
no more than one DLT observed in the previous cohort (see Section 3.1.9). 
The second subject in each cohort should not start treatment until the first subject has completed early 
engraftment (approximately Day 12 to 18 post ASCT); therefore, the first subject in each cohort will 
receive the first dose of tremelimumab 75 mg or durvalumab 1500 mg + tremelimumab 75 mg and 
will be observed for a period of 7 weeks for toxicities before the next subject is enrolled.   
Enrollment into the cohorts will be monitored for safety on an ongoing basis according to Section 
3.1.14. 
3.1.3 Blinding/Unblinding 
This is an open-label study. 
3.1.4 Subject Population 
Subjects with high risk or relapsed multiple myeloma eligible for autologous stem cell transplant 
(ASCT) and with available cryopreserved stem cells. 
For complete eligibility details, see Section 5.  
3.1.5 No. of Sites/Subjects 
The study will accrue up to 6 subjects in each cohort and will be performed at 2 sites. 
3.1.6 Sample Size Considerations 
A sample size of 6 subjects in each of the cohorts is deemed to be sufficient for the assessment of 
safety and tolerability as the primary objective and the exploration of clinical anti-tumor activity and 
other secondary and exploratory endpoints.  


 
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Subjects will not be treated as part of the next cohort unless a DLT was observed in no more than 1 
out of the 6 subjects in the previous cohort during the DLT observation period. Using this design, 
initiation of the next cohort is probable if the risk of DLT is low, and the likelihood of initiation 
decreases as the risk of DLT increases, as demonstrated in Table 1. 
Table 1. Cohort Initiation/Toxicity Risk 
True Risk of Toxicity 
.10 
.20 
.30 
.40 
.50 
.60 
Probability of Cohort Initiation 
.88 
.66 
.42 
.23 
.11 
.04 
 
Within each cohort of 6 subjects, the confidence interval of estimating the incidence of AEs of special 
interest (i.e., symptomatic and/or irreversible treatment-related Grade 4 pneumonitis, colitis, 
dermatitis, or hepatitis or any symptomatic treatment-related related Grade ≥3 neurological toxicity 
or uveitis) are provided in Table 2. 
Table 2. Confidence Intervals 
Number of Subjects 
with Event 
Incidence 
95% Exact Confidence Interval 
(Clopper Pearson) 
1/6 
0.17 
(0.004, 0.64) 
2/6 
0.33 
(0.04, 0.77) 
3/6 
0.50 
(0.12, 0.88) 
4/6 
0.67 
(0.22, 0.96) 
5/6 
0.83 
(0.36, 0.99) 
 
3.1.7 Treatment Cohorts and Treatment Schema 
The study will consist of 4 cohorts; see Table 3, Figure 1, Figure 2, Figure 3, and Figure 4.  Cohort 
enrollment will be sequential so that Cohort 1 will be treated first, followed by a safety review before 
each subsequent cohort will be opened. Subjects will not be treated as part of a new cohort until all 
subjects in the previous cohort have completed the DLT observation period, and there was no more 
than one DLT observed in the previous cohort (see Section 3.1.9). 
The second subject in each cohort should not start treatment until the first subject has completed early 
engraftment (approximately Day 12 to 18 post ASCT); therefore, the first subject in each cohort will 
receive the first dose of tremelimumab 75 mg or durvalumab 1500 mg + tremelimumab 75 mg and 
will be observed for a period of 7 weeks for toxicities before the next subject is enrolled. 
The 4 cohorts (see Table 3) are based on subjects receiving tremelimumab 75 mg alone (Cohorts 1 
and 2) or durvalumab 1500 mg + tremelimumab 75 mg (Cohorts 3 and 4) prior to and for 2 cycles 
post autologous stem cell transplant (ASCT) as well as 2 different schedules of post ASCT therapy 
(late [Cohorts 1 and 3] and early [Cohorts 2 and 4]) as described below. 
Subjects in each cohort will receive a single dose of tremelimumab 75 mg alone (Cohorts 1 and 2) or 
a single dose of durvalumab 1500 mg + tremelimumab 75 mg (Cohorts 3 and 4) on Day -31.  The first 
dose is given 21 days prior to steady state leukopheresis, which occurs on Day -10 to Day -3 for the 
collection of autologous peripheral blood lymphocytes (PBLs).   
Note: a dose of Prevnar-13 will be given on Day -33 ± 2 days; however, the Prevnar-13 dose and the 
tremelimumab 75 mg dose on Day -31 must be separated by a minimum of 48 hours).  Two 


 
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additional doses of Prevnar-13 will be given during the period following HDT/ASCT according to 
flowchart in Section 3.2. 
Leukopheresis will be followed by high dose therapy (HDT, melphalan 200 mg/m2 IV according to 
institution practice) on Day -2 and autologous stem cell transplant (ASCT), using previously banked 
hematopoietic stem cells, on Day 0 of the study.   
Autologous PBLs will be infused into subjects on Day +3 following ASCT.  A single dose of 
tremelimumab 75 mg will be administered on the same day (within 24 hours) after the end of the 
PBL infusion. 
Following HDT/ASCT, treatment will resume with tremelimumab 75 mg alone (Cohorts 1 and 2) or 
durvalumab 1500 mg + tremelimumab 75 mg (Cohorts 3 and 4) for the first 2 cycles post HDT/ASCT 
according to the following schedule: 
• 
Late Post ASCT Treatment: 
o Cohort 1 - tremelimumab 75 mg alone on Day 100 (±10) and 4 weeks later (Cycles 1 and 2) 
o Cohort 3 –- tremelimumab 75 mg+ durvalumab 1500 mg on Day 100 (±10) and 4 weeks later 
(Cycles 1 and 2) 
• 
Early Post ASCT Treatment: 
o Cohort 2- tremelimumab 75 mg alone on Day 30-40 and Day 100 (±10) (Cycles 1 and 2) 
o Cohort 4 – tremelimumab 75 mg + durvalumab 1500 mg on Day 30-40 and Day 100 (±10) 
(Cycles 1 and 2) 
For Cycles 3 to 8, durvalumab alone (1500 mg Q4W) will continue to be administered for all cohorts.  
Cycle 3 will start 28 days after Cycle 2 dose, and it will start no later than Day 156 (±4 days) for 
Cohorts 1 and 3; it will start no later than Day 128 (±4 days) for Cohorts 2 and 4.  
Note for durvalumab fixed dosing: 
The durvalumab fixed dosing is for subjects who weigh > 30 kg.  If a subject’s body weight drops to 
≤ 30 kg while on the study, the subject will be dosed at 600 mg for durvalumab as long as the body 
weight remains ≤ 30 kg.   
Note for enrollment into Cohorts 2 and 4 
For subjects in Cohort 2 or 4, if Day 30 administration of study drug is delayed for >10 days due to 
extended recovery from transplant related toxicities, then the Cycle 1 dose of study medication can 
be administered to that subject on Day 100 (±10), at the Investigator’s discretion and following a 
discussion with the Medical Monitor.  The timing of further dosing and assessments for that subject 
should then follow the dosing schema for Cohort 1 or 3, respectively. The subject(s) originally 
scheduled for Cohort 2 or 4 will be replaced. If this situation occurs for 3 or more subjects in Cohort 2 
or 4, the cohort will be considered not feasible and will be closed. If Cohort 2 is deemed not feasible, 
Cohort 4 will also be considered not feasible. 
 


 
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Table 3: Tremelimumab and Durvalumab Treatment Schema for Cohorts 1 to 4 
Cohorts 
Cohort 1 
T only  
and Late 
Treatment 
Cohort 2 
T only 
and Early 
Treatment 
Cohort 3 
T + D 
and Late 
Treatment 
Cohort 4 
T + D 
and Early 
Treatment 
Cycle 
Day 
Tremelimumab 75 mg only  
(T) 
Tremelimumab 75 mg + 
Durvalumab 1500 mg (T + D) 
Pre ASCT 
Day -31 
T 
T 
T + D 
T + D 
PBL  
Day 3 
T + PBL 
T + PBL 
T + PBL 
T + PBL 
Cycle 1  
Post ASCT 
Late 
Day 100±10 
T 
 
T + D 
 
Early 
Day 30-40 
 
T 
 
T + D 
Cycle 2  
Post ASCT 
Late 
Cycle 1 +28 days 
T 
 
T + D 
 
Early 
Day 100±10 
 
T 
 
T + D 
Cycles 3 to 8 
28 days post 
Cycle 2 
Durvalumab Q4W  
 
 
 
Figure 1: Treatment Schema for Cohort 1 
 


 
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Figure 2: Treatment Schema for Cohort 2 
 
 
 
Figure 3: Treatment Schema for Cohort 3 
 
 


 
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Figure 4: Treatment Schema for Cohort 4 
 
3.1.8 Dosing Adjustments, Delays and Discontinuations 
Durvalumab and tremelimumab administration may be modified or discontinued as a result of 
toxicities as described in Section 8.3. 
3.1.9 Dose Limiting Toxicity (DLT) and MTD/RCD 
MTD/RCD will not be determined for this study. 
There will be an ongoing overall safety assessment according to Section 3.1.14.   
DLTs will be assessed for the period from the first study drug administration up to and including the 
Cycle 2 administration (Day 128 for Cohorts 1 and 3 or Day 100 for Cohorts 2 and 4) of tremelimumab 
or tremelimumab + durvalumab post ASCT, defined as the DLT Evaluation Period, for each subject in 
Cohorts 1 through 4. Subjects will not be treated as part of a new cohort until all subjects in the 
previous cohort have completed the DLT Evaluation Period, and there was no more than one DLT 
observed in the previous cohort. DLTs occurring outside the DLT Evaluation Period will also be 
evaluated and may impact such decisions. 
The occurrence of any of the below toxicities during the DLT Evaluation Period as defined above will 
be considered a DLT:  
1) Delayed engraftment: Neutrophil engraftment will be defined as the first of 3 consecutive 
assessments with absolute neutrophil count >500/mm3.  Platelet engraftment will be defined 
as the first of 3 consecutive assessments of platelets >20,000/mm3 without platelet 
transfusion in the prior 7 days.  Engraftment will be considered delayed (and therefore a DLT) 
if the subject has not met criteria for both neutrophil and platelet engraftment by Day 30 
after ASCT. 
2) Grade 5 toxicity, treatment-related death. 
3) Grade 4 toxicity, other than hematological toxicity. 


 
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4) Grade 3 toxicity, other than hematological toxicity, fever, chills, dyspnea, infection, fatigue, 
abdominal pain, diarrhea, dysphagia, oral mucositis, oral pain, flu-like syndrome, pain, 
anorexia, dehydration, glucose intolerance, hypocalcemia, hypokalemia, hypomagnesemia, 
hyponatremia, hypophosphatemia, pain in extremity, headache, insomnia, hypoxia, dry skin, 
pruritus, hypertension, and hypotension. 
5) Isolated Grade 3 electrolyte abnormalities (i.e., those occurring without clinical 
consequence), except those that resolve, with or without intervention, to <Grade 2 within 72 
hours. 
6) Any immune-related adverse event (irAE) that results in discontinuation from study 
treatment. See Section 8.3 for irAEs and dose adjustments due to durvalumab and 
tremelimumab. See Section 7.1.8 for adverse events of special interest. 
 
IrAEs are defined as adverse events (AEs) of immune nature (i.e., inflammatory) in the absence of a 
clear alternative etiology. In the absence of clinical abnormality, repeat laboratory testing will be 
conducted to confirm significant laboratory findings prior to designation as a DLT. 
While rules for adjudicating DLTs are specified above, an AE may also be defined as a DLT after 
consultation with the Sponsor and Investigators, based on the emerging safety profiles of 
tremelimumab and durvalumab.  Likewise, subjects who become not evaluable for DLT, because they 
discontinued or interrupted treatment due to toxicities other than DLTs, may be counted as DLT 
subjects, if the toxicities cannot be managed in accordance with the dosing modifications described 
in Section 3.1.8 
Subjects who experience a DLT will be discontinued from study treatment and will enter the On 
Study and Post Study Follow-up phases of the study (see Section 3.1.16).  However, if it is in the best 
interest of the subject, the Investigator and Sponsor may agree to continue treatment, possibly at a 
lower dose level or discontinue one or more of the study drugs. 
3.1.10 Subject Withdrawal from Treatment or from Study 
A subject will be withdrawn from study treatment for any of the following reasons: 
1. Withdrawal of consent for further treatment 
2. Pregnancy or intent to become pregnant. 
3. Confirmation of symptomatic progressive disease by International Myeloma Working Group 
(IMWG) uniform response criteria. (87, 88) Subjects may be treated beyond asymptomatic 
progression if the Investigator believes there is potential for clinical benefit and the case is 
discussed with the Medical Monitor. 
4. Significant protocol violation or noncompliance that, in the opinion of the Investigator or 
Sponsor, warrants withdrawal. 
5. Development of intercurrent, non-cancer-related illnesses or complications that prevent 
either continuation of therapy or regular follow-up. 
6. Best medical interest of the subject (at the discretion of the Investigator) 
 


 
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A subject will be withdrawn from the study for the following reasons: 
1. Best medical interest of the subject at the discretion of the Investigator  
2. Initiation of alternative anticancer therapy (marketed or investigational agent). 
3. Withdrawal of consent for all follow-up. 
4. Lost to follow-up. 
5. Death. 
Discontinuation from receiving study treatment does not mean that the subject is withdrawn from 
the study.  If applicable, subjects who are withdrawn from study treatment should undergo the 
planned On Study Follow-up procedures followed by the Post Study follow-up period (see Section 3.2 
and Section 3.1.16). 
See also Section 8.3 for subject withdrawal from treatment due to necessary dosing interruptions or 
discontinuations. 
Section 7.2.6 provides additional details regarding documentation for early subject withdrawal from 
study treatment and early withdrawal from study.  
3.1.11 Subject Evaluability and Replacement  
Subjects are fully evaluable for DLT if they fulfill the criteria for the Per-Protocol Population for DLT 
Assessment (as defined in Section 4.1.2). 
Subjects who are not fully evaluable for DLT per Section 4.1.2 will be replaced. 
Note: See Section 3.1.7 note for replacement of subjects in Cohorts 2 and 4 if Day 30 administration 
of study drug is delayed for >10 days due to extended recovery from transplant related toxicities. 
3.1.12 Optional Study Treatment Extension 
Treatment extensions beyond what is outlined in the protocol are not planned. 
3.1.13 Interim Analysis 
No formal interim analysis will be performed.  Analyses will be performed to assess safety and 
tolerability on an ongoing basis throughout the study (Section 3.1.14) and DLTs will be assessed as 
part of the DLT Evaluation Period (Section 3.1.9).   
3.1.14 Safety Monitoring and Study Stopping Rules 
In accordance with the Administrative, Legal and Ethical Requirements (Section 7) of the protocol, 
Safety Monitoring will be performed by an internal data safety monitoring panel, consisting of the 
Principal Investigators (and co-investigators as needed), the Sponsor Medical Monitor, and drug 
safety personnel from MedImmune, the providers of the two study drugs.  Additional Investigators 
and staff, or additional Sponsor personnel and consultants, shall participate in reviews as indicated.  
The safety monitoring panel will communicate by phone and/or email on a regular basis, and in 
particular, to review the safety of individual cohorts before the next cohort is initiated. 
An Independent Data Monitoring Board will not be utilized for this open-label study. 


 
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Page 22 of 79 
The study will be suspended and possibly stopped for any of the following reasons: 
(1) Death in any subject in which the cause of death is unexpected and assessed as at least 
probably related to durvalumab, tremelimumab, and/or PBL reinfusion. 
(2) Severe anaphylactic reaction to durvalumab, tremelimumab, and/or PBL reinfusion (i.e., with 
respiratory and cardiovascular failure) in any subject. 
(3) Any events that, in the judgment of the Medical Monitor, are deemed serious enough to 
warrant immediate review by the data safety monitoring panel. This may include any 
symptomatic and/or irreversible treatment-related grade 4 pneumonitis, colitis, dermatitis, 
or hepatitis or any symptomatic treatment-related related grade ≥3 neurological toxicity 
or uveitis. 
(4) Any other safety finding that, in the opinion of the internal data safety monitoring panel, 
contraindicates further dosing of study subjects. 
(5) Any interim findings that, in the opinion of the Investigators and the Sponsor, suggest that 
the study treatment has no clinical benefit for the subjects. 
Study stopping rules may be applied to individual cohorts, if the data safety monitoring panel 
concludes that the identified risk to one cohort does not carry over to another. 
General criteria for premature trial termination are outlined in Section 7.2.7.  
3.1.15 Duration of Study 
Enrollment Period: 
24 months  
Duration of Treatment 
11 months 
Length of Study: 
35 months 
Post Study Follow-up 
24 months from initiation of treatment 
 
End of study is defined as the date of the last protocol-specified visit/assessment for the last subject 
in the study or the date the study is closed by the Sponsor, whichever occurs first. 
3.1.16 On Study and Post Study Follow-up 
All subjects, whether they complete the study as planned, discontinue treatment, or prematurely 
withdraw from the study per Sections 3.1.10 and/or 7.2.6, will be followed according to institutional 
guidelines in accordance with the usual standard of care principles.   
For subjects who complete the study or who discontinue treatment prematurely, On Study Follow-up 
will be conducted for 90 days after the last study drug administration according to the flowchart in 
Section 3.2.  Refer to Section 7.1.5 for information on recording AEs during the On Study Follow-up. 
If the determination is made to remove a subject from treatment at a visit that coincides with the 
first visit of the On Study Follow-up Period (which is 28 days after the last dose of study treatment), 
any assessments required in the first On Study Follow-up visit that are not covered as part of the last 
on-treatment visit (usually correlative labs) should be done as soon as possible.  If these assessments 
cannot be done on the same day, the subject should be brought back in at the earliest opportunity.  
Any assessments or correlative samples required by both the last on-treatment visit and the first On 
Study Follow-up visit should not be repeated. 


 
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Page 23 of 79 
In addition to the On Study Follow-up, there will be a Post Study Follow-up, during which clinical 
outcomes data (dates of progression/relapse, subsequent therapy, and survival) will be collected at 
least once every 6 months for up to 2 years from initiation of treatment.  
The Post Study Follow-up will include a query to determine if there were any immune-related 
adverse events (irAEs) during the 90 days since the last administration of study drug. 
For subjects who do not continue Post Study Follow-up- at one of the study sites after the end of 
study, the Principal Investigators or the clinical team, under the supervision of the Principal 
Investigator, will obtain these data through review of outside records or communication with the 
subject or his/her physician. 
 End of Study Visit 
If a subject is withdrawn from study according to the criteria defined in Section 3.1.10, an End of 
Study visit must be conducted at the time of withdrawal. For subjects who are not yet in On Study 
Follow-up, this End of Study visit will be the first planned visit of the On Study Follow-up. For subjects 
who are already in On Study Follow-up, this End of Study visit will be the next planned visit of the On 
Study Follow-up. However, any procedures/assessments that were done within 7 days of the End of 
Study visit need not be repeated. All subjects of childbearing potential who withdraw from study 
must have a serum pregnancy test done at the End of Study visit, unless it was done within 7 days 
prior to the End of Study Visit. 
After the End of Study Visit, the subject will proceed into Post Study Follow-up as described above, 
unless otherwise unable to do so (e.g., subject withdraws consent for all follow-up).  
 


 
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Page 24 of 79 
3.2 Study Flowchart 
 
PBL
Cycle 1
Cycle 2
Treatment  weeks (based on ASCT)
-9 to -5
2
5
9
14
18
Cycle Day
1
1
Treatment days (based on ASCT)
-62 to -34
-33±2
-31±2
-10 to -3
-2
0
3 
12 ±4
30 +10
60±4
100±10
128±4
Tremelimumab (75 mg)
x1
x2
X
X
Durvalumab (1500  mg)
X8
X8
X8
HDT - Melphalan (200 mg/m2 IV) 
x
Autologous Stem cell transplant (ASCT)
x
Peripheral blood lymphocyte (PBL) pheresis 
x
PBL infusion
x2
Prevnar - 13
x1
x1
x1
FDG PET/CT scan or MRI spine (As clinically indicated 
to evaluate for plasmacytoma(s) or soft tissue 
disease)
x
x
Myeloma serum tests (SPEP, sFLC, Quantitative Igs, 
Serum IF,  beta-2 microglobulin)5
x
x
x
x
Myeloma urine tests (Total protein, Creatinine, 
UPEP, Urine IF)5  (24-hour as applicable)
x
x
x
x
Informed Consent (IC) and Eligibility Assessment9
x
Demographics (incl. DoB; sex; height; race; 
ethnicity)
x
Physical Exam (incl. weight)
x
x
x
x
x
x
x
x
x
x
x
x
Medical history 
x
ECOG Performance Status
x
x
x
x
x
x
x
x
x
x
x
x
Vital Signs (T, HR, BP, RR) (see Section 6.5 for vital 
signs during infusion)
x
x
x
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
ECHO 
x
Pulmonary function test  with DLCO
x
Concomitant Medication (name, indication, dose, 
route, start & end dates)/Concomitant  Procedures
x
x
x
 x
x
x
x
x
x
x
x
x
Adverse Events (starting or worsening after IC)10 
x
x
x
x
x
x
x
x
x
x
x
x
Blood Hematology (complete blood count with 
differential & platelets & other parameters as 
clinically indicated; e.g., reticulocytes, blasts, etc.)3
-40 to -33
x
x
x
x
x
x
x
x
x
x
x
Chemistry (gluc, BUN, creat, Na, K, Ca, Mg, Cl, CO2, 
protein, alb., Tbili., AST, ALT, LDH, ALP)3
-40 to -33
x
x
x
x
x
x
x
x
x
x
x
Chemistry cont. (Amylase and lipase)3
-40 to -33
x
x
x
x
x
x
x
x
x
x
x
Endocrine panel (TSH, Free T3,Free T4, cortisol, 
ACTH)3
-40 to -33
x
x
Coagulation
-40 to -33
x
x
x
x
x
x
x
x
x
x
x
Urinalysis
-40 to -33
x
x
x
x
x
x
x
x
x
x
x
Serum pregnancy test (urine test only on Day -31)3
-40 to -33
x
x
x
x
x
Trephine biopsy for antigen IHC
x
x
Immune monitoring (banked BMMCs, flow 
cytometry, functional assays, immunodiversity)
x
x
Minimal residual disease testing
x
x
PBMC: Immune monitoring (flow cytometry, 
functional assays, immunodiversity)
x
x3
x4
x3
x
x3
x3
x3
x3
Tumor antigen specific serology
x3
x4
x
x3
x3
x3
x3
Pneumococcal serology
x3
x4
x
x3
x3
x3
x3
Circulating soluble factors (cytokines, chemokines, 
auto-antibodies)
x3
x
x3
DNA/RNA profiling
x3
x
x3
Myeloid Derived Suppressor Cells
x
x3
x
x3
x3
Overall Survival
Progression Free Survival6
1. Prevnar dose  and tremelimumab dose must be separated by a minimum of 48 hrs.
2. Tremelimumab must be infused within 24 hours following PBL infusion
3. Collect pre-dose  (prior to drug administration) or other infusion.  Note: It is strongly recommended that hematology, 
     chemistry and pregnancy test (when applicable) results are reviewed before dosing.
4. Samples will be removed from the pheresis product
5. If serum and urine IF are positive, subsequent analysis is not necessary unless the subject achieves a response of VGPR or greater
7. Cycle 3 will start 28 days after Cycle 2 dose, and it will start no later than Day 156 for Cohorts 1 and 3
8. Pre-ASCT and Cycle1 and Cycle 2 Durvalumab dose for Cohort 3 only 
9. Standard of Care procedures may be used for eligibility assessments provided they meet the criteria specified in either the inclusion criteria or flowchart
10. See section 7.1.5 for details regarding collection of AEs for 90 days after last study drug administration
6. For subjects who did not experience progression while on study             
HDT /ASCT
1
Bone Marrow Samples
Whole Blood for Correlative Testing
Long-Term Follow-up
Post ASCT and PBL 
Study Drugs and PBL  Administration
Disease Assessments by IMWG uniform response criteria
Study Procedures and Examinations
Routine Laboratory Samples
Study Flowchart for Cohorts 1 and 3
- Late Post Tx Cohorts
Screening / 
Baseline
Pre ASCT
Treatment 


 
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LUD2014-010 Protocol Amendment 3 (Final, 28-MAR-2017) 
Page 25 of 79 
 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle6
Cycle 7
Cycle 8
Treatment  weeks (based on ASCT)
22
26
30
34
38
42
Cycle Day
1
1
1
1
1
1
Treatment days (based on ASCT)
156 ±4
184 ±4
212 ±4
240 ±4
268 ±4
296±4
Tremelimumab (75 mg)
Durvalumab (1500  mg)
X7
X
X
X
X
X
HDT - Melphalan (200 mg/m2 IV) 
Autologous Stem cell transplant (ASCT)
Peripheral blood lymphocyte (PBL) pheresis 
PBL infusion
Prevnar - 13
FDG PET/CT scan or MRI spine (As clinically indicated 
to evaluate for plasmacytoma(s) or soft tissue 
disease)
x
Myeloma serum tests (SPEP, sFLC, Quantitative Igs, 
Serum IF,  beta-2 microglobulin)5
x
x
x
x
x
x
x
x
x
Myeloma urine tests (Total protein, Creatinine, 
UPEP, Urine IF)5  (24-hour as applicable)
x
x
x
x
x
x
x
x
x
Informed Consent (IC) and Eligibility Assessment9
Demographics (incl. DoB; sex; height; race; 
ethnicity)
Physical Exam (incl. weight)
x
x
x
x
x
x
x
x
x
Medical history 
ECOG Performance Status
x
x
x
x
x
x
x
x
x
Vital Signs (T, HR, BP, RR) (see Section 6.5 for vital 
signs during infusion)
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
ECHO 
Pulmonary function test  with DLCO
Concomitant Medication (name, indication, dose, 
route, start & end dates)/Concomitant  Procedures
x
x
x
x
x
x
x
x
x
Adverse Events (starting or worsening after IC)10 
x
x
x
x
x
x
x
x
x
Blood Hematology (complete blood count with 
differential & platelets & other parameters as 
clinically indicated; e.g., reticulocytes, blasts, etc.)3
x
x
x
x
x
x
x
x
x
Chemistry (gluc, BUN, creat, Na, K, Ca, Mg, Cl, CO2, 
protein, alb., Tbili., AST, ALT, LDH, ALP)3
x
x
x
x
x
x
x
x
x
Chemistry cont. (Amylase and lipase)3
x
x
x
x
x
x
x
x
x
Endocrine panel (TSH, Free T3,Free T4, cortisol, 
ACTH)3
x
x
x
x
Coagulation
x
x
x
x
x
x
x
x
x
Urinalysis
x
x
x
x
x
x
x
x
x
Serum pregnancy test (urine test only on Day -31)3
x
x
x
x
x
Trephine biopsy for antigen IHC
x
Immune monitoring (banked BMMCs, flow 
cytometry, functional assays, immunodiversity)
x
Minimal residual disease testing
x
PBMC: Immune monitoring (flow cytometry, 
functional assays, immunodiversity)
x3
x3
x3
x
x
x
Tumor antigen specific serology
x3
x3
x3
x
x
x
Pneumococcal serology
x3
x3
x
x
x
Circulating soluble factors (cytokines, chemokines, 
auto-antibodies)
x3
x3
x3
x
x
DNA/RNA profiling
x3
x3
Myeloid Derived Suppressor Cells
x3
x3
x3
x
x
Overall Survival
x
Progression Free Survival6
x
1. Prevnar dose  and tremelimumab dose must be separated by a minimum of 48 hrs.
2. Tremelimumab must be infused within 24 hours following PBL infusion
3. Collect pre-dose  (prior to drug administration) or other infusion.  Note: It is strongly recommended that hematology, 
     chemistry and pregnancy test (when applicable) results are reviewed before dosing.
4. Samples will be removed from the pheresis product
5. If serum and urine IF are positive, subsequent analysis is not necessary unless the subject achieves a response of VGPR or greater
6. For subjects who did not experience progression while on study             
7. Cycle 3 will start 28 days after Cycle 2 dose, and it will start no later than Day 156 for Cohorts 1 and 3
8. Pre-ASCT and Cycle1 and Cycle 2 Durvalumab dose for Cohort 3 only 
9. Standard of Care procedures may be used for eligibility assessments provided they meet the criteria specified in either the inclusion criteria or flowchart
10. See section 7.1.5 for details regarding collection of AEs for 90 days after last study drug administration
On Study Follow-up
Post Study 
Follow-up 
Every 6 
months for up 
to 2 years from 
start of 
treatment
Bone Marrow Samples
Whole Blood for Correlative Testing
Long-Term Follow-up
Last study 
drug +28  
±4 days
Last study 
drug +56 
±4 days
Last study 
drug +91 
±4 days 
End of Study
Study Drugs and PBL  Administration
Disease Assessments by IMWG uniform response criteria
Study Procedures and Examinations
Routine Laboratory Samples
Study Flowchart for Cohorts 1 and 3
- Late Post Tx Cohorts (cont)
Treatment 


 
C O N F I D E N T I A L  
SOP-C01-TMP-3 version 3  
LUD2014-010 Protocol Amendment 3 (Final, 28-MAR-2017) 
Page 26 of 79 
 
PBL
Cycle 1
Cycle 2
Treatment  weeks (based on ASCT)
-9 to -5
2
5
9
14
Cycle Day
1
Treatment days (based on ASCT)
-62 to -34
-33±2
-31±2
-10 to -3
-2
0
3 
12 ±4
30 +10
60±4
100 ±10
Tremelimumab (75 mg)
x1
x2
X
X
Durvalumab (1500  mg)
X8
X8
X8
HDT - Melphalan (200 mg/m2 IV)
x
Autologous Stem cell transplant (ASCT)
x
Peripheral blood lymphocyte (PBL) pheresis 
x
PBL infusion
x2
Prevnar - 13
x1
x1
x1
FDG PET/CT scan or MRI spine (As clinically indicated 
to evaluate for plasmacytoma(s) or soft tissue 
disease)
x
x
Myeloma serum tests (SPEP, sFLC, Quantitative Igs, 
Serum IF, beta-2 microglobulin)5
x
x
x
Myeloma urine  tests (Total protein, Creatinine, 
UPEP, Urine IF)5  (24-hour as applicable)
x
x
x
Informed Consent (IC) and Eligibility Assessment9
x
Demographics (incl. DoB; sex; height; race; 
ethnicity)
x
Physical Exam (incl. weight)
x
x
x
x
x
x
x
x
x
x
x
Medical history
x
ECOG Performance Status
x
x
x
x
x
x
x
x
x
x
x
Vital Signs (T, HR, BP, RR) (see Section 6.5 for vital 
signs during infusion)
x
x
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
ECHO 
x
Pulmonary function test  with DLCO
x
Concomitant Medication (name, indication, dose, 
route, start & end dates)/Concomitant Procedures
x
x
x
 x
x
x
x
x
x
x
x
Adverse Events (starting or worsening after IC)10 
x
x
x
x
x
x
x
x
x
x
x
Blood Hematology (complete blood count with 
differential & platelets & other parameters as 
clinically indicated; e.g., reticulocytes, blasts, etc.)3
-40 to -33
x
x
x
x
x
x
x
x
x
x
Chemistry (gluc, BUN, creat, Na, K, Ca, Mg, Cl, CO2, 
protein, alb., Tbili., AST, ALT, LDH, ALP)3
-40 to -33
x
x
x
x
x
x
x
x
x
x
Chemistry cont. (Amylase and lipase)3
-40 to -33
x
x
x
x
x
x
x
x
x
x
Endocrine panel (TSH, Free T3,Free T4, cortisol, 
ACTH)3
-40 to -33
x
x
Coagulation
-40 to -33
x
x
x
x
x
x
x
x
x
x
Urinalysis
-40 to -33
x
x
x
x
x
x
x
x
x
x
Serum pregnancy test (urine test only on Day -31)3
-40 to -33
x
x
x
x
x
Trephine biopsy for antigen IHC
x
x
Immune monitoring (banked BMMCs, flow 
cytometry, functional assays, immunodiversity)
x
x
Minimal residual disease testing
x
x
PBMC: Immune monitoring (flow cytometry, 
functional assays, immunodiversity)
x
x3
x4
x3
x
x3
x3
x3
Tumor antigen specific serology
x3
x4
x
x3
x3
x3
Pneumococcal serology
x3
x4
x
x3
x3
x3
Circulating soluble factors (cytokines, chemokines, 
auto-antibodies)
x3
x
DNA/RNA profiling
x3
x
Myeloid Derived Suppressor Cells
x
x3
x
x3
Overall Survival
Progression Free Survival6
1. Prevnar dose  and tremelimumab dose must be separated by a minimum of 48 hrs.
2. Tremelimumab must be infused within 24 hours following PBL infusion
3. Collect pre-dose  (prior to drug administration) or other infusion. Note: It is strongly recommended that hematology, 
     chemistry and pregnancy test (when applicable) results are reviewed before dosing.
4. Samples will be removed from the pheresis product
5. If serum and urine IF are positive, subsequent analysis is not necessary unless the subject achieves a response of VGPR or greater
7. Cycle 3 will start 28 days after Cycle 2 dose, and it will start no later than Day 128 for Cohorts 2 and 4
8. Pre-ASCT and Cycle1 and Cycle 2 Durvalumab dose for Cohort 4 only 
9. Standard of Care procedures may be used for eligibility assessments provided they meet the criteria specified in either the inclusion criteria or flowchart
10. See section 7.1.5  for details regarding collection of AEs for 90 days after last study drug administration
6. For subjects who did not experience progression while on study             
Long-Term Follow-up
1
Study Drugs and PBL  Administration
Disease Assessments by IMWG uniform response criteria
Study Flowchart for Cohorts 2 and 4
- Early Post Tx Cohorts
Screening / 
Baseline
Pre ASCT
HDT /ASCT
Treatment 
Whole Blood for Correlative Testing
Study Procedures and Examinations
Routine Laboratory Samples
Bone Marrow Samples


 
C O N F I D E N T I A L  
SOP-C01-TMP-3 version 3  
LUD2014-010 Protocol Amendment 3 (Final, 28-MAR-2017) 
Page 27 of 79 
 
Cycle 3
Cycle 4
Cycle 5 
Cycle 6
Cycle 7
Cycle 8
Treatment  weeks (based on ASCT)
18
22
26
30
34
38
Cycle Day
1
1
1
1
1
1
Treatment days (based on ASCT)
128±4
156 ±4
184 ±4
212 ±4
240 ±4
268 ±4
Tremelimumab (75 mg)
Durvalumab (1500  mg)
X7
X
X
X
X
X
HDT - Melphalan (200 mg/m2 IV)
Autologous Stem cell transplant (ASCT)
Peripheral blood lymphocyte (PBL) pheresis 
PBL infusion
Prevnar - 13
FDG PET/CT scan or MRI spine (As clinically indicated 
to evaluate for plasmacytoma(s) or soft tissue 
disease)
x
Myeloma serum tests (SPEP, sFLC, Quantitative Igs, 
Serum IF, beta-2 microglobulin)5
x
x
x
x
x
x
x
x
x
Myeloma urine  tests (Total protein, Creatinine, 
UPEP, Urine IF)5  (24-hour as applicable)
x
x
x
x
x
x
x
x
x
Informed Consent (IC) and Eligibility Assessment9
Demographics (incl. DoB; sex; height; race; 
ethnicity)
Physical Exam (incl. weight)
x
x
x
x
x
x
x
x
x
Medical history
ECOG Performance Status
x
x
x
x
x
x
x
x
x
Vital Signs (T, HR, BP, RR) (see Section 6.5 for vital 
signs during infusion)
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
ECHO 
Pulmonary function test  with DLCO
Concomitant Medication (name, indication, dose, 
route, start & end dates)/Concomitant Procedures
x
x
x
x
x
x
x
x
x
Adverse Events (starting or worsening after IC)10 
x
x
x
x
x
x
x
x
x
Blood Hematology (complete blood count with 
differential & platelets & other parameters as 
clinically indicated; e.g., reticulocytes, blasts, etc.)3
x
x
x
x
x
x
x
x
x
Chemistry (gluc, BUN, creat, Na, K, Ca, Mg, Cl, CO2, 
protein, alb., Tbili., AST, ALT, LDH, ALP)3
x
x
x
x
x
x
x
x
x
Chemistry cont. (Amylase and lipase)3
x
x
x
x
x
x
x
x
x
Endocrine panel (TSH, Free T3,Free T4, cortisol, 
ACTH)3
x
x
x
x
Coagulation
x
x
x
x
x
x
x
x
x
Urinalysis
x
x
x
x
x
x
x
x
x
Serum pregnancy test (urine test only on Day -31)3
x
x
x
x
x
Trephine biopsy for antigen IHC
x
Immune monitoring (banked BMMCs, flow 
cytometry, functional assays, immunodiversity)
x
Minimal residual disease testing
x
PBMC: Immune monitoring (flow cytometry, 
functional assays, immunodiversity)
x3
x3
x3
x3
x
x
x
Tumor antigen specific serology
x3
x3
x3
x3
x
x
x
Pneumococcal serology
x3
x3
x3
x
x
x
Circulating soluble factors (cytokines, chemokines, 
auto-antibodies)
x3
x3
x3
x3
x
x
DNA/RNA profiling
x3
x3
x3
Myeloid Derived Suppressor Cells
x3
x3
x3
x3
x
x
Overall Survival
x
Progression Free Survival6
x
1. Prevnar dose  and tremelimumab dose must be separated by a minimum of 48 hrs.
2. Tremelimumab must be infused within 24 hours following PBL infusion
3. Collect pre-dose  (prior to drug administration) or other infusion. Note: It is strongly recommended that hematology, 
     chemistry and pregnancy test (when applicable) results are reviewed before dosing.
4. Samples will be removed from the pheresis product
5. If serum and urine IF are positive, subsequent analysis is not necessary unless the subject achieves a response of VGPR or greater
6. For subjects who did not experience progression while on study             
7. Cycle 3 will start 28 days after Cycle 2 dose, and it will start no later than Day 128 for Cohorts 2 and 4
8. Pre-ASCT and Cycle1 and Cycle 2 Durvalumab dose for Cohort 4 only 
9. Standard of Care procedures may be used for eligibility assessments provided they meet the criteria specified in either the inclusion criteria or flowchart
10. See section 7.1.5  for details regarding collection of AEs for 90 days after last study drug administration
Long-Term Follow-up
Last study 
drug +91 
±4 days 
End of Study
Study Drugs and PBL  Administration
Disease Assessments by IMWG uniform response criteria
Study Flowchart for Cohorts 2 and 4
- Early Post Tx Cohorts (cont)
On Study Follow-up
Post Study 
Follow-up 
Every 6 
months for up 
to 2 years from 
start of 
treatment
Last study 
drug +28  
±4 days
Treatment 
Whole Blood for Correlative Testing
Last study 
drug +56 
±4 days
Study Procedures and Examinations
Routine Laboratory Samples
Bone Marrow Samples


 
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4 
Study Objectives and Endpoints 
Primary 
Objectives 
[Endpoints] 
Safety and Tolerability of durvalumab/tremelimumab [DLTs, AEs 
according to CTCAE version 4.03]. 
Secondary 
Objectives  
[Endpoints] 
Clinical efficacy [response by IMWG criteria, minimal residual disease 
assessment, one-year PFS and OS, 100-day ASCT related mortality]. 
Exploratory 
Objective 
[Endpoints] 
Biological Activity [Gene expression, mutation analysis, and protein 
expression of immune regulation markers of tumor cell populations. 
Effects of PBL and durvalumab / tremelimumab combination on 
immune reconstitution, T and B cell receptor diversity, and immune 
responses to Prevnar-13 and myeloma antigens]. 
DLT=Dose-limiting Toxicity; AE=adverse event; PFS=Progression-free Survival; OS=Overall Survival; 
CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; IMWG=International 
Myeloma Working Group; ASCT=Autologous stem cell transplant; PBL=Peripheral blood lymphocytes 
In order to be fully evaluable (per protocol) for the primary endpoint, major protocol violations 
that interfere with the assessment of the primary endpoint must be absent. 
4.1 Safety and Tolerability 
Assessment of safety and tolerability of the regimens will be performed by the internal data 
safety monitoring panel on an ongoing basis, based on data review and regular conference calls 
with the Investigators as described in Section 3.1.14.  The safety and tolerability of each regimen 
will be evaluated using DLT criteria (Section 3.1.9).  
4.1.1 Endpoints and Assessment Methods 
Clinical laboratory tests, vital sign assessments, physical exams and any other medically 
indicated assessments and subject interviews will be performed to detect new abnormalities 
and deteriorations of any pre-existing conditions.  The investigator will evaluate any laboratory 
abnormalities for clinical significance, and clinically significant abnormalities will be recorded as 
adverse events.  All treatment-emergent clinically significant abnormalities and deteriorations 
that begin or worsen in severity after initial administration of durvalumab and/or tremelimumab 
should be recorded in the Case Report Forms (CRFs) as AEs and graded according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.  See 
further adverse event documentation and reporting requirements in Section 7.1. 
4.1.2 Subject Evaluation and Statistics 
The Per-Protocol (PP) Population for DLT Assessment includes: 
• 
All subjects who experience a DLT at any time during the DLT Evaluation Period (as 
defined in Section 3.1.9) 
• 
All subjects with no DLT who receive at least 75% of the scheduled doses of durvalumab 
and tremelimumab (according to the respective cohort requirements), receive all 
associated transplant procedures per standard of care, and undergo respective safety 
assessments without major protocol violations over the entire DLT Evaluation Period (as 
defined in Section 3.1.9)  


 
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See Section 3.1.11 for subject evaluability and replacement for DLT assessments.  
The Safety Population is defined as all subjects who receive at least 1 dose of durvalumab or 
tremelimumab. The overall analysis of safety and tolerability will be based on the Safety 
Population. 
Appropriate summaries of AEs, SAEs, laboratory data and vital signs data will be presented.  
Adverse events will be coded using the MedDRA dictionary.  Incidences of treatment-emergent 
adverse events (TEAE, those events that started after dosing or worsened in severity after 
dosing) will be presented overall and by maximum severity and relationship to study 
medication.  Adverse events will be listed individually per subject according to CTCAE version 
4.03, and the number of subjects experiencing each AE will be summarized using descriptive 
statistics.   
For each continuous laboratory parameter, results will be categorized as low, normal, or high 
based on the laboratory normal ranges. Frequencies and percentages will be presented for the 
shifts in these categories (i.e., low to normal, low to high, high to low, etc.) from baseline to 
each post-treatment assessment time point. Additionally, for each continuous hematology and 
chemistry parameter, descriptive statistics will be presented for the changes from baseline to 
each post-treatment assessment time point. Descriptive statistics will be presented for the 
changes in vital signs from baseline to each post-treatment assessment time point.  
4.2 Clinical Efficacy  
4.2.1 Endpoints and Assessment Methods 
Clinical efficacy evaluation will include tumor response assessed by IMWG uniform response 
criteria for myeloma, 100-day post ASCT mortality rate, minimal residual disease assessment, 
one-year progression-free survival (PFS), and overall survival (OS). 
 Multiple Myeloma Response Assessment by IMWG Consensus Criteria 
Response will be evaluated using the IMWG consensus criteria for uniform response 
assessments in clinical trials.(87, 88) Tumor Response by IMWG criteria is defined as PR, VGPR, 
CR or stringent CR.  Stable disease is defined as not meeting criteria for response or progression. 
See Section 8.4 for definitions. 
 100-Day Post Autologous Stem Cell Transplant Mortality Rate  
Subjects’ survival status will be reported on Day 100 following ASCT.  
 Minimal Residual Disease Assessment 
Bone marrow assessments at 100 days and approximately 1-year post ASCT (Day 324 ± 4 days) 
will include evaluation of minimal residual disease by flow cytometry and genetic methods as 
noted in Section 3.2. 
 Progression-Free Survival (PFS) 
One-year PFS (Day 324 ± 4 days) will be determined for each subject with time origin at the start 
of the ASCT treatment (Day 0) until the first occurrence of confirmed progression by IMWG 


 
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criteria or date of death if the subject dies from any causes before progression.  Every effort will 
be made to follow subjects for progression after the last study drug administration.  Long-term 
follow-up will continue for up to 2 years from start of treatment as described in Section 3.1.16. 
All four cohorts will be combined when estimating PFS.  
 Overall Survival (OS) 
Overall survival (OS) will be measured for each subject with time origin at the start of the ASCT 
treatment (Day 0) until recorded date of death.  Every effort will be made to follow subjects for 
overall survival after the last study drug administration.  Long-term follow-up will continue for 
up 2 years from start of treatment as described in Section 3.1.16.  All four cohorts will be 
combined when estimating OS.  
4.2.2 Subject Evaluation and Statistics 
All subjects who received at least one dose of durvalumab and/or tremelimumab, as well as 
baseline and at least one post-baseline disease assessment, will be evaluated for clinical 
efficacy.  Tumor Responses by IMWG, PFS, and OS will be summarized and analyzed 
descriptively. 
4.3 Biological Activity  
4.3.1 Endpoints and Assessment Methods 
Samples for exploratory assessments will be collected at each visit and time points as noted in 
Section 3.2. Assessments include but may not be limited to the assays listed below. 
 Circulating Soluble Factors (Cytokine Profiling) 
Blood samples at baseline and following protocol treatment will be collected for analyses of 
circulating levels of soluble factors such as CRP, cytokines and chemokines. They may include but 
are not limited to markers such as soluble CD80/86, soluble IL-6R, VEGF, FGF, IL-1 IL-2, IL-4, IL-6, 
IL-8, IL-10, soluble CTLA-4, granzyme B, IFN, LARGE, CXCL10, SOCS3, APRIL, BAFF, IGF-1, IGF-2, and 
autoantibodies to host, tumor, or pneumococcal antigens and explore their association with 
treatment and clinical outcome. 
 Pneumococcal Serology 
Antibody responses to pneumococcal serotypes 1, 3, 4, 6B, 7F, 8, 9V, 14, 18C, 19F, 23F will be 
measured using a commercially available reagent (Focus Diagnostics, Cypress, CA). Prevnar-13 
contains antigen to all serotypes except 8, which allows for an internal negative control for 
vaccine. 
 PBMC/BMMC Banking 
Peripheral Blood Mononuclear Cells (PBMCs), serum, and bone marrow mononuclear cells 
(BMMC) will be isolated and banked as described below at time points designated in Section 3.2. 
Peripheral blood mononuclear cells and bone marrow samples will be collected to assess 
immune cell phenotypes that may include T cell phenotype and activation markers, B cells, 


 
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myeloid derived suppressor cells and/or immune diversity. These samples may be used to 
address several key questions: 
• 
The diversity of the immune cell repertoire may be assessed in PBMCs and bone marrow 
aspirate, if feasible based on VDJ coding region analysis to determine if clinical responses 
are correlated with immunodiversity and if repertoire changes occur in response to 
treatment.   
• 
Functional assays such as ELISPOT or tetramer staining or intracellular cytokine analysis may 
be employed to assess the activation state or antigen specificity of immune cell populations 
in the periphery.  
• 
Flow cytometric analyses to examine additional markers not included in our primary panel 
may be performed on banked samples to supplement our understanding of a subject’s 
immune status.   
 Flow cytometry for Immune Reconstitution (Immune monitoring) 
Peripheral blood populations before and after treatment, including absolute lymphocyte counts, 
numbers of T cells, T-cell subsets, NK cells, B cells, and monocytes as well as their cellular 
phenotypes will be assessed by Flow cytometry to evaluate the association with treatment and 
subject responses. 
 Bone Marrow Biopsies 
Consent for bone marrow biopsies is mandatory for all subjects, if clinically appropriate.  
Samples will be collected for immunohistochemistry (IHC) and additional correlative markers. 
Biopsy samples will be examined to evaluate the correlation between clinical activity, the 
expression level of PD-L1 on myeloma cells and tumor infiltrating macrophages, and tumor-
infiltrating lymphocytes changes in biopsies pre and post treatment. 
Bone marrow biopsy will be performed during screening and as indicated for subjects in 
Section 3.2.  
Bone marrow samples (collected pre-treatment and/or post treatment) will be examined to 
evaluate biomarkers by dual color immunohistochemistry (IHC) and genomic techniques. This 
may include but is not limited to, the expression level and localization of immunosuppressive 
proteins such as PD-L1 on tumor cells and tumor infiltrating macrophages, tumor infiltrating 
lymphocytes (TILs), and/or markers of inflammatory/immune cell signatures, e.g. CTLA-4 CD3, 
CD4, CD8, CD45RO, IFN-gamma, FoxP3, and granzyme B and OX40. Any relationships between 
biomarker expression with subject response to treatment will be evaluated.  Additionally, 
analyses of tumor mutations and polymorphisms may be performed through relevant 
methodologies in order to assess genetic alterations and their potential relationships with 
treatment outcome. Further, selected gene sequencing of samples may be employed to 
evaluate genetic alterations and relationships with treatment outcome with durvalumab and 
tremelimumab. 
 Additional translational and exploratory studies 
Optional research studies may only be performed for subjects who voluntarily gave their 
consent for additional correlative research on the informed consent document.  Subjects who 
declined consent to participate in additional translational studies will have their samples 


 
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destroyed at the end of the study.  Refusal to participate in this optional research will involve no 
penalty or loss of benefits to which the subject would otherwise be entitled.   Based on the data 
generated during the study and/or in other studies, not all samples from subjects consenting to 
this optional research may be utilized. 
 Genomic Profiling 
Whole blood samples, bone marrow mononuclear cells, and bone marrow samples will be 
collected pre/post treatment and preserved for possible future genomic analyses for, but not 
limited to somatic mutations, expression of tumor antigens, inflammatory cytokines / 
chemokines, or other factors.  These analyses may be conducted to generate hypotheses 
associated with the mechanisms of action of immunotherapy and/or to identify subsets of 
subjects responsive to durvalumab and tremelimumab. 
4.3.2 Subject Evaluation and Statistics 
Only subjects who received at least one dose of tremelimumab (Cohorts 1 and 2) or one dose of 
both durvalumab and tremelimumab (Cohorts 3 and 4), and provided the baseline and at least 
one post-treatment sample (if applicable), will be evaluated.   
The exploratory pharmacodynamic assessment of the immunologic changes in the bone marrow 
will include the correlation between clinical activity and the expression level of PD-L1 and 
tumor-infiltrating lymphocytes (TILs) changes in bone marrow biopsies pre and post treatment. 
Subjects will be classified as responders or non-responders based on IMWG.  Within each 
response group, subjects’ plasma cells will be assessed as positive or negative for PD-L1 
expression.  For the purpose of this exploratory analysis, Fisher’s Exact Test will be used to 
assess whether there is an association between responder-status and PD-L1 
expression.  Confidence intervals for the overall odds ratio and the odds ratio within each cohort 
will be presented.  The association between response and TILs changes (increase, decrease, or 
no change) will be evaluated similarly.  
All other exploratory results will be summarized descriptively. 


 
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5 
Subject Eligibility 
Note: Standard of Care procedures may be used for eligibility assessments provided they meet 
the criteria specified in either the inclusion criteria or flowchart. 
5.1 Inclusion Criteria 
Eligible subjects must fulfill all of the following criteria: 
1.  Histologically confirmed multiple myeloma 
2. 
Measurable disease either at enrollment, prior to most recent line of salvage therapy, 
or prior to most recent line of induction therapy. Measurable disease is defined by any 
of the following: 
• 
Serum M-spike ≥ 0.5 g/dL 
• 
Serum free light chain ≥ 10mg/dL 
• 
Urine monoclonal protein ≥200 mg/24 hours 
• 
Multifocal plasmacytoma 
• 
≥ 20% bone marrow plasmacytosis 
3. 
Available CD34+ stem cells (≥2x106/kg) 
4. 
Eligible for autologous stem cell transplantation. 
5. 
Four or less prior lines of systemic therapy for multiple myeloma* 
*Induction, 1st ASCT, consolidation, and maintenance are considered 1 line of therapy 
unless treatment was modified due to progression of disease (POD) as defined by 
IMWG criteria 
6. 
Able and willing to provide consent for required bone marrow biopsies. 
7. 
ECOG performance status of 0-1. 
8. 
Anticipated lifespan greater than 3 months. 
9. 
Adequate organ function, as defined below: 
• 
Total bilirubin within normal ranges unless associated with hepatobiliary 
metastases or Gilbert syndrome, then total bilirubin ≤ 2 x ULN 
• 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x 
ULN  
• 
Creatinine ≤ 2.0 mg/dL 
• 
DLCO ≥50% 
10. 
Have been informed of other treatment options. 
11. 
Age ≥ 18 years. 
12. 
Able and willing to give valid written informed consent. 
13. 
Body weight > 30 kg. 
 
 


 
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5.2 Exclusion Criteria 
Subjects may not enter the study if they fulfill any of the following criteria: 
1. 
Prior exposure to tremelimumab or durvalumab or other anti-CTLA-4, anti-PD-1, anti-
PD-L1 antibodies 
2. 
History of severe allergic reactions to any unknown allergens or any components of the 
study drugs. 
3. 
Active or prior autoimmune disease except for autoimmune thyroiditis, vitiligo, or 
psoriasis not requiring systemic therapy. 
4. 
Prior allogeneic transplantation 
5. 
Any prior Grade ≥ 3 immune-related adverse event (irAE) or any prior corticosteroid-
refractory irAE. 
6. 
Known active or chronic viral hepatitis or history of any type of hepatitis within the last 
6 months. 
7. 
History of sarcoidosis syndrome. 
8. 
Active or history of inflammatory bowel disease (colitis, Crohn’s), celiac disease, or 
other serious, chronic, gastrointestinal conditions associated with diarrhea. Active or 
history of systemic lupus erythematosus or Wegener’s granulomatosis. 
9. 
Metastatic disease to the central nervous system for which other therapeutic options, 
including radiotherapy, may be available. 
10. 
Known immunodeficiency or active HIV. 
11. 
Other active serious illnesses (e.g., serious infections requiring antibiotics). 
12. 
Prior treatment in any other clinical trial involving another investigational agent within 
4 weeks prior to Day -31 of the study; resolution of respective adverse event to Grade 1 
or lower should have occurred. (See Section 5.3.1 for standard of care therapy). 
13. 
Major surgical procedure (as defined by the Investigator) within 30 days prior to 
Day -31 or still recovering from prior surgery. 
14. 
Mental impairment that may compromise the ability to give informed consent and 
comply with the requirements of the study. 
15. 
Lack of availability for immunological and clinical follow-up assessments. 
16. 
Women who are breastfeeding or pregnant as evidenced by positive serum pregnancy 
test (minimum sensitivity 25 IU/L or equivalent units of HCG)  
17. 
Female subjects of childbearing potential who are sexually active with a nonsterilized 
male partner must use at least one highly effective method of contraception (see table 
below) from the time of screening, and must agree to continue using such precautions 
for 90 days after the last dose of durvalumab or for 6 months after the last dose of 
tremelimumab (whichever is longer). Non-sterilized male partners of a female subject 
must use male condoms plus spermicide throughout this period. Cessation of birth 
control after this point should be discussed with a responsible physician. Not engaging 
in sexual activity for the total duration of the trial and the drug washout period is an 
acceptable practice; however, periodic abstinence, the rhythm method, and the 
withdrawal method are not acceptable methods of birth control. 


 
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Female subjects should refrain from breastfeeding throughout the period described 
above. 
Females of childbearing potential are defined as those who are not surgically sterile 
(i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or 
postmenopausal.   
Females will be considered post-menopausal if they have been amenorrheic for 12 
months without an alternative medical cause.  The following age-specific requirements 
apply:  
• 
Females <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution or underwent surgical 
sterilization (bilateral oophorectomy or hysterectomy).  
• 
Females ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or underwent 
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or 
hysterectomy.  
Women of childbearing potential must have a negative serum b-HCG pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of HCG) conducted during screening 
and a negative urine b-HCG pregnancy test conducted prior to study drug 
administration on Day -31.  Ongoing serum pregnancy tests will be conducted according 
to the study flowchart in Section 3.2. 
Nonsterilized male subjects who are sexually active with a female partner of 
childbearing potential must use male condoms plus spermicide from screening through 
90 days after last dose of durvalumab or through 6 months after the last dose of 
tremelimumab (whichever is longer).  Female partners (of childbearing potential) of a 
male subject must use a highly effective method of contraception (see table below) 
throughout the period described above. Cessation of birth control after this point 
should be discussed with a responsible physician. Not engaging in sexual activity for the 
total duration of the trial and the drug washout period is an acceptable practice; 
however, periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception. 
Male subjects should refrain from sperm donation throughout this period. 
Highly effective methods of contraception are described in the table below. A highly 
effective method of contraception is defined as one that results in a low failure rate (i.e. 
less than 1% per year) when used consistently and correctly. Note that some 
contraception methods are not considered highly effective (e.g. male or female condom 
with or without spermicide; female cap, diaphragm, or sponge with or without 
spermicide; non-copper containing intrauterine device; progestogen-only oral hormonal 
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[excluding Cerazette/desogestrel which is considered highly effective]; and triphasic 
combined oral contraceptive pills). 
Acceptable highly effective methods of contraception are described in the following 
table: 
Highly Effectivea Methods of Contraception 
Barrier/Intrauterine Methods 
Hormonal Methods 
• 
Copper T intrauterine device 
• 
Levonorgesterel-releasing intrauterine 
system (e.g., Mirena®)b 
• “Implants”: Etonogestrel-releasing 
implants: e.g., Implanon® or Norplan®  
• “Intravaginal Devices”: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices: e.g., NuvaRing®   
• “Injection”: Medroxyprogesterone 
injection: e.g., Depo-Provera®   
• “Combined Pill”: Normal and low dose 
combined oral contraceptive pill 
• “Patch”: Norelgestromin / 
ethinylestradiol-releasing transdermal 
system: e.g., Ortho Evra®    
• 
“Minipillc”: Progesterone based oral 
contraceptive pill using desogestrel: e.g., 
Cerazette® 
a - Highly effective (i.e. failure rate of <1% per year)  
b - This is also considered a hormonal method 
c - Cerazette® is currently the only highly effective progesterone based pill 
18. 
Any condition that, in the clinical judgment of the treating physician, is likely to prevent 
the subject from complying with any aspect of the protocol or that may put the subject 
at unacceptable risk. 
19. 
Subjects must not donate blood while on study and for at least 90 days following the 
last durvalumab treatment or for 6 months following the last tremelimumab treatment, 
whichever is longer. 
 


 
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5.3 Restrictions on Concomitant Therapies 
5.3.1 Non-Permitted Concomitant Therapies 
Subjects may not receive the following concomitant therapies during the study: 
1. 
Systemic treatment with high dose corticosteroids (greater than Prednisone 10 mg daily 
or equivalent) or other immunosuppressive treatments (e.g. methotrexate, 
chloroquine, azathioprine).  See Section 5.3.2 for exceptions. 
Wash-out period: 2 weeks prior to Day -31. 
2. 
Other cancer therapy (chemotherapy, radiation or immunotherapy). 
Wash-out period: 4 weeks or 5 half-lives (whichever is shorter) prior to Day -31; 6 
weeks for nitrosoureas. 
3. 
Live/attenuated vaccines 1 month prior to Day -31 and for at least 6 months after the 
last dose of treatment. 
4. 
Sunitinib within 3 months after the last dose of tremelimumab. 
5. 
Palifermin, leuprolide acetate, or denosumab 1 month prior or 1 month after the last 
treatment on study. 
6. 
Drugs with laxative properties and herbal or natural remedies for constipation should 
be avoided through 90 days post last dose of tremelimumab because of the potential 
for exacerbation of diarrhea. 
5.3.2 Permitted Concomitant Therapies 
Subjects may receive the following concomitant therapies during the study: 
1. 
Inhaled or oral steroids for treating mild to moderate asthma or allergies, or topical 
steroids for localized (< 10% of body surface area) dermatitis. 
2. 
Antihistamines and other non-steroidal anti-allergy medication. 
3. 
Hormone or hormone-related anti-cancer therapy. 
4. 
Maintenance dose lenalidomide 
5. 
At the discretion of the Investigator, any drug or non-drug therapy necessary to treat 
any condition arising during the study, including high dose corticosteroids and TNF-α 
inhibitors to treat adverse reactions. 
All prescription and nonprescription drugs must be recorded in the concomitant medications 
section of the case report form, listing generic (preferably) or brand name, indication, dose, 
route and dates of administration.  All non-drug therapies must be recorded in the respective 
sections of the Case Report Form. 


 
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6 
Study Drugs Preparation and Administration 
All study drugs are manufactured in accordance with Good Manufacturing Practices (GMP).  
On the days when durvalumab and tremelimumab are to be administered together, durvalumab 
infusion will start at least 60 minutes after the end of tremelimumab infusion.  On study drug 
administration days, vital sign assessments will be recorded according to the table in Section 
6.5. 
When Prevnar-13 is given, the Prevnar-13 dose and the tremelimumab dose must be separated 
by a minimum of 48 hours. 
On the day of PBL infusion (Day 3 after ASCT), tremelimumab will be infused over a minimum of 
60 ± 5 minutes after the end of the PBL infusion (within 24 hours).   
6.1 Durvalumab (MEDI4736) 
Durvalumab is supplied by the Sponsor.  Commercially available 0.9% (w/v) saline or 5% (w/v) 
dextrose will be supplied by each site.  See Section 7.2.8 for additional details. 
6.1.1 Study Drug Information 
Manufacturer 
MedImmune 
Expiration/Retest Date 
Expiration/retest dates are documented in the QA Disposition 
of Investigational Medicinal Product (IMP) Report. 
Container Description 
Type: 
Single use vial  
 
Clear glass 
Size: 
10 mL 
Formulation 
Durvalumab for infusion is supplied as a vialed liquid solution 
containing 500 mg (nominal) durvalumab per vial. The solution 
contains 50 mg/mL durvalumab, 26 mM histidine/histidine HCl, 
275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, at 
pH 6.0 
Active Ingredient Content 
Mass/Weight: 
500 mg 
Volume: 
10 mL 
Concentration: 
50 mg/mL 
Storage Conditions 
2°C to 8°C (36°F to 46°F) Do not freeze 
Labeling 
Product name, lot number, route of administration, and 
storage conditions 
6.1.2 Durvalumab Investigational Product Inspection 
Each vial of durvalumab selected for dose preparation should be inspected.  If there are any 
defects noted with the investigational product (IP), the Investigator and Sponsor should be 
notified immediately. 
6.1.3 Durvalumab Preparation 
Preparation of durvalumab and preparation of the intravenous bag are to be performed 
aseptically by the IP manager or designated personnel.  No incompatibilities between 
durvalumab and polyvinylchloride or polyolefin copolymers have been observed. 


 
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Dose Calculation: 
Subjects will receive a fixed dose of durvalumab: 1500 mg for subjects > 30 kg.  If a subject’s 
body weight drops to ≤ 30 kg while on the study, the subject will be dosed at 600 mg for 
durvalumab as long as the body weight remains ≤ 30 kg. 
The volume of durvalumab (in mL) to be added to the IV bag is calculated as follows: 
Volume of 
Durvalumab 
(mL) 
= 
Dose level (mg) 
÷ 
Durvalumab 
Concentration (nominal 
50 mg/mL) 
 
Dose Preparation: 
Durvalumab will be administered using a 250 mL IV bag containing 0.9% (w/v) saline or 5% (w/v) 
dextrose, and delivered through an IV administration set with a 0.2 or 0.22 µm in-line filter.  A 
volume of diluent equal to the calculated volume of durvalumab to be added to the IV bag must 
be removed from the bag prior to addition of durvalumab.  The calculated volume of 
durvalumab is then added to the IV bag, and the bag is mixed by gentle inversion to ensure 
homogeneity of the dose in the bag.   
Example: For a 1500 mg dose (for subjects > 30 kg in weight), 30 mL of durvalumab is to be 
diluted in a 250 mL IV bag. First, 30.0 mL of diluent is removed from the IV bag, and then 30 mL 
of durvalumab is added to the bag.  The bag is mixed by gentle inversion to ensure homogeneity 
of the dose in the bag and the diluted durvalumab is administered as described below. 
Durvalumab does not contain preservatives; any unused portion must be discarded.  
6.1.4 Durvalumab Administration 
Following preparation of the dose, durvalumab will be administered according to the following 
guidelines: 
• 
A physician must be present at the site or immediately available to respond to 
emergencies during all administrations of investigational product(s). Fully functional 
resuscitation facilities should be available. 
• 
Durvalumab must not be administered via IV push or bolus but as an IV infusion. 
• 
Durvalumab solution should not be infused with other solutions or medications. 
• 
Durvalumab must be administered at room temperature by controlled infusion into a 
peripheral vein or central line.  
• 
Prior to the start of the infusion, the IV bag contents must be at room temperature to 
avoid an infusion reaction due to the administration of the solution at low 
temperatures. 
• 
The entire contents of the IV bag should be administered as an IV infusion over 
approximately 60 ± 5 minutes, using a 0.2- or 0.22-μm in-line filter.  An infusion of less 
than 55 minutes is considered a deviation. 
• 
After the contents of the IV bag are fully administered, the IV line will be flushed with a 
volume of IV diluent equal to the priming volume of the infusion set used.  Alternatively, 


 
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the infusion will be completed according to institutional policy to ensure the full dose is 
administered; documentation is required if the line was not flushed. 
• 
The total time between needle puncture of the durvalumab vial to start of 
administration should not exceed 4 hours at room temperature or 24 hours at 2°C to 
8°C (36°F to 46°F). Standard infusion time is 60 ± 5 minutes. However, if there are 
interruptions during infusion (total infusion time not to exceed 4 hours), the total 
allowed time for preparation and administration should not exceed 8 hours at room 
temperature.  In the event that either preparation time or infusion time exceeds the 
time limits, a new dose must be prepared from new vials. 
• 
The date, start time, interruption, and completion time of durvalumab administration 
must be recorded in the source documents.  
• 
Subjects will be monitored before, during and after infusion with assessment of vital 
signs according to Section 6.5. 
• 
See Section 8.3.1 for guidelines for infusion-related reactions. 
 
6.2 Tremelimumab  
6.2.1 Study Drug Information  
Manufacturer 
MedImmune 
Expiration/Retest Date 
Expiration/retest dates are documented in the QA Disposition of 
IMP Report 
Container Description 
Type: 
Single use vial  
Material: 
clear glass 
Size: 
20 mL 
Formulation 
Liquid solution containing 400 mg tremelimumab per vial.  
The solution contains 20 mg/mL tremelimumab, 20 mM 
histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 
0.27 mM disodium edetate dihydrate, and 0.02% 
weight/volume (w/v) polysorbate 80; it has a pH of 5.5. 
Active Ingredient Content 
Mass/Weight: 
400 mg/vial 
Volume: 
20 mL 
Concentration: 
20 mg/mL 
Storage Conditions 
2°C to 8°C (36°F to 46°F) Do not freeze 
Labeling 
Product name, lot number, route of administration, and storage 
conditions 
6.2.2 Tremelimumab Investigational Product Inspection 
Each vial of tremelimumab selected for dose preparation should be inspected.  If there are any 
defects noted with the investigational product (IP), the Investigator and Sponsor should be 
notified immediately. 
6.2.3 Tremelimumab Preparation 
The dose of tremelimumab for administration must be prepared by the IP manager or 
designated personnel using aseptic technique. No incompatibilities between tremelimumab and 


 
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polyvinylchloride or polyolefin have been observed. However, administration sets containing 
cellulose-based filters should not be used with tremelimumab. 
Dose Calculation: 
Subjects will receive a fixed dose of tremelimumab: 75 mg.   
The volume of tremelimumab (in mL) to be added to the IV bag is calculated as follows: 
Tremelimumab 
Dose (mL) 
= 
dose level (mg) 
÷ 
Tremelimumab concentration  
(20 mg/mL) 
 
Dose Preparation: 
Tremelimumab will be administered using a 250 mL IV bag containing 0.9% (w/v) saline or 5% 
(w/v) dextrose, and delivered through an IV administration set with a 0.2- or 0.22-μm in-line 
filter.  The calculated volume of tremelimumab is added to the IV bag, and the bag is mixed by 
gentle inversion to ensure homogeneity of the dose in the bag. 
Example: The volume of tremelimumab required for 75 mg dose is 3.75 mL.  
The corresponding volume of investigational product should be rounded according to 
institutional practice. For example, (for a 75 mg dose of tremelimumab), if the institutional 
practice is to round the volume to the nearest tenth mL, 3.75 mL would be rounded to 3.8 mL, 
which would be the volume of tremelimumab added to the bag; the bag is then mixed by gentle 
inversion. 
Tremelimumab does not contain preservatives and any unused portion must be discarded.  
6.2.4 Tremelimumab Administration 
Following preparation of the dose, tremelimumab will be administered according to the 
following guidelines: 
• 
A physician must be present at the site or immediately available to respond to 
emergencies during all administrations of investigational product. Fully functional 
resuscitation facilities should be available. 
• 
Prior to the start of the infusion, the IV bag contents must be at room temperature to 
avoid an infusion reaction due to the administration of the solution at low 
temperatures. 
• 
Tremelimumab must be administered at room temperature (25°C) by controlled 
infusion into a peripheral vein or central line.   
• 
Tremelimumab solution should not be infused with other solutions or medications.  
• 
Tremelimumab must not be administered via IV push or bolus but as a slow IV infusion. 
• 
The entire contents of the IV bag should be administered as an IV infusion over 
approximately 60 (±5) minutes, using a 0.2, or 0.22-μm in-line filter. An infusion of less 
than 55 minutes is considered a deviation. 
• 
After the contents of the IV bag are fully administered, the IV line will be flushed with a 
volume of IV diluent equal to the priming volume of the infusion set used.  Alternatively, 


 
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the infusion will be completed according to institutional policy to ensure the full dose is 
administered; documentation is required if the line was not flushed. 
• 
The total time from needle puncture of the tremelimumab vial to the start of 
administration should not exceed 4 hours at room temperature or 24 hours at 2 to 8°C 
(36°F to 46°F). Standard infusion time is 60 ± 5 minutes. However, if there are 
interruptions during infusion (total infusion time not to exceed 4 hours), the total 
allowed time for preparation and administration should not exceed 8 hours at room 
temperature.  In the event that either preparation time or infusion time exceeds the 
time limits, a new dose must be prepared from new vials. 
• 
The date, start time, interruption, and completion time of tremelimumab administration 
must be recorded in the source documents.  
• 
Subjects’ vital signs will be monitored before, during and after infusion as indicated in 
Section 6.5. 
• 
See Section 8.3.1 for guidelines for infusion-related reactions. 
6.3 Estimated Study Drug Requirements 
Estimated drug requirements for the study are summarized in the following table: 
Drug 
Required Quantity 
Durvalumab 
540 vials 
Tremelimumab  
96 vials  
6.4 Drug Overdose Management 
An overdose is defined as a subject receiving a dose of investigational product in excess of that 
specified in this protocol by >10%.  There are no known antidotes available for durvalumab or 
tremelimumab.  Any overdoses with these drugs should be managed symptomatically and 
reported, with or without associated AEs/SAEs, according to Section 7.1.2.2. 
6.5 Monitoring of Tremelimumab and Durvalumab Dose 
Administration 
Subjects will be monitored during and after infusion with assessment of vital signs according to 
the table below: 
Vital Signs Assessment on Study Drug Administration Days 
Drug 
Pre Dose 
During Infusion 
End of Infusion  
(± 5 minutes) 
30 (± 5) Minutes 
Post Infusion  
60 (± 5) Minutes 
Post Infusion  
Tremelimumab 
X 
Every 30 (± 5) 
minutes 
X 
 
 
Durvalumab  
X 
Every 15 (± 5) 
minutes 
X 
X 
X 


 
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Note: When durvalumab and tremelimumab are to be administered on the same day, 
durvalumab infusion will start at least 60 minutes after the end of tremelimumab infusion even 
though vital signs assessment is not required during the entire 60 minute period post 
tremelimumab. 
If a subject tolerates treatment well for the first 4 doses of durvalumab (i.e., no infusion 
reactions), subsequent infusions in that subject can be monitored according to the table below.  
A longer duration of observation after the end of infusion can be used if the Investigator deems 
it clinically necessary. 
Vital Signs Assessment 
on study drug 
administration days 
(after first 4 doses) 
Pre Dose 
During Infusion 
End of Infusion  
(± 5 minutes) 
15 (± 5) Minutes 
Post Infusion 
Durvalumab 
X 
Every 30 (± 5) 
minutes 
X 
X 
 


 
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7 
Administrative, Legal and Ethical Requirements 
7.1 Documentation and Reporting of Adverse Events 
7.1.1 Definitions 
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with the treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. 
N.B.: The definition above, provided for in the GCP-ICH Guideline E6, is being extended for the 
purpose of Ludwig Institute for Cancer research (LICR) studies to include any events, 
intercurrent diseases and accidents observed while the subject is on study, i.e., during the actual 
treatment period, as well as during drug-free, pre- and post-treatment periods, under placebo 
or in a reference group receiving drug or non-drug therapy or no treatment.   
A Serious Adverse Event (SAE) is any untoward medical occurrence that: 
1. 
Results in death, 
2. 
Is life-threateningA, 
3. 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
4. 
Results in persistent or significant disability or incapacity, 
5. 
Is a congenital anomaly / birth defect or 
6. 
Is another medically important conditionB. 
A 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject is at risk of death at the time of the event; it does not refer to an event, which 
hypothetically might have caused death if it were more severe. 
B 
Medically important conditions that may not result in death, be immediately life-
threatening or require hospitalization may be considered as SAE when, based upon appropriate 
medical judgment, they may jeopardize the subject or may require intervention to prevent one 
of the outcomes listed in the definition above.  Examples of such events are intensive treatment 
in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization; or development of drug dependency or drug abuse. 
N.B.: The term “severe” is often used to describe the intensity (severity) of an event (such as: 
mild, moderate, or severe, e.g., pain).  The event itself may be of relatively minor medical 
significance (such as severe headache).  This is not the same as “serious”, which is based on 
subject/event outcome or action criteria usually associated with events that pose a threat to 
subject’s life or vital functions.  Seriousness (not severity) serves as a guide for defining 
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7.1.2 Additional Expedited Reporting Requirements for this Study 
For the purpose of this study, the following events must be reported by phone or email to the 
Sponsor within 24 hours of knowledge of the event (see Section 7.1.6 for Sponsor contact 
information) and may result in submission of an SAE based on certain criteria outlined below: 
1. Pregnancy 
2. Overdose (as defined in Section 6.4) 
3. Hepatic Function Abnormality (as defined in Section 7.1.8) 
 Pregnancy 
7.1.2.1.1 Maternal Exposure 
Female subjects should avoid becoming pregnant and breastfeeding during the study and for 
90 days after the last dose of durvalumab or for 6 months after the last dose of tremelimumab 
(whichever is longer). 
If a subject becomes pregnant during the course of the study, the study drugs should be 
discontinued immediately.   
Pregnancy itself is not regarded as an AE unless there is a suspicion that the drug under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities or birth defects and spontaneous miscarriages should be reported and handled as 
SAEs (see Section 7.1.6).  Elective abortions without complications should not be handled as AEs.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) should be followed up and documented 
even if the subject was discontinued from the study.   
If any pregnancy occurs in the course of the study, the Investigator or other site personnel 
should inform the Sponsor (see Section 7.1.6 for Sponsor contact information) within 1 day, i.e., 
immediately, but no later than 24 hours of when he or she becomes aware of it.   
The Sponsor will work with the Investigator to ensure that all relevant information is provided 
within 1 to 5 calendar days for SAEs and within 30 days for all other pregnancies.   
The same timelines apply when outcome information is available. 
7.1.2.1.2 Paternal Exposure 
Male subjects should refrain from fathering a child or donating sperm during the study and for 
90 days after the last dose of durvalumab or for 6 months after the last dose of tremelimumab 
(whichever is longer).   
Pregnancy of the subject’s partner is not considered to be an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 90 days after the last dose 
should, if possible, be followed up and documented.   
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the Investigator must obtain the consent of the subject’s partner.  Therefore, the local study 


 
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team should adopt the generic ICF template in line with local procedures and submit it to the 
relevant Ethics Committees (ECs)/Institutional Review Boards (IRBs) prior to use.  
 Overdose 
Any overdose (as defined in Section 6.4) of a study subject, with or without associated AEs/SAEs, 
is required to be reported within 24 hours of knowledge of the event to the Sponsor (see 
Section 7.1.6 for Sponsor contact information). If the overdose results in an AE, the AE must also 
be recorded as an AE according to Section 7.1.5. Overdose does not automatically make an AE 
serious, but if the consequences of the overdose are serious, for example death or 
hospitalization, the event is serious and must be recorded and reported as an SAE according to 
Section 7.1.6. There is currently no specific treatment in the event of an overdose of 
durvalumab or tremelimumab. The Investigator will use clinical judgment to treat any overdose. 
See Section 6.4 for additional details. 
 Hepatic Function Abnormality 
Hepatic function abnormality (as defined in Section 7.1.8) in a study subject, with or without 
associated clinical manifestations, is required to be reported as “hepatic function abnormal” 
within 24 hours of knowledge of the event to the Sponsor, unless a definitive underlying 
diagnosis for the abnormality (e.g., cholelithiasis or bile duct obstruction) that is unrelated to 
investigational product has been confirmed (see Section 7.1.6 for Sponsor contact information). 
• 
If the definitive underlying diagnosis for the abnormality has been established and is 
unrelated to investigational product, the decision to continue dosing of the study 
subject will be based on the clinical judgment of the investigator. 
• 
If no definitive underlying diagnosis for the abnormality is established, dosing of the 
study subject must be interrupted immediately. Follow-up investigations and inquiries 
must be initiated by the investigational site without delay. 
Each reported event of hepatic function abnormality will be followed by the Investigator and 
evaluated by the Sponsor and MedImmune/AstraZeneca. 
7.1.3 Severity of an Adverse Event 
The severity of all serious and non-serious adverse events should be assessed according to the 
National Cancer Institute CTCAE Scale (Version 4.03). 
7.1.4 Relationship of Adverse Events to Study Drug 
The relationship of all serious and non-serious AEs to the investigational agent(s) will be 
determined by the Investigator on the basis of his/her clinical judgment, using one of the 
following terms (in accordance with NCI Guideline “Expedited Adverse Event Reporting 
Requirements for NCI Investigational Agents”, NCI Cancer Therapy Evaluation Program, January 
2001): 
Definitely related (The AE is clearly related to the investigational agent) 
Probably related (The AE is likely related to the investigational agent) 
Possibly related (The AE may be related to the investigational agent) 
Unlikely related (The AE is doubtfully related to the investigational agent) 


 
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Unrelated (The AE is clearly not related to the investigational agent) 
N.B.: When making the assessment on causality, it should be taken into consideration that 
immune-therapeutic agents have the potential to cause very late and/or permanent effects on 
the immune system, i.e., a causal relationship could exist despite a lack of apparent temporal 
relationship.  Information provided in the IB and/or in “Background” of this protocol may 
support these evaluations. 
7.1.5 General Reporting Requirements 
All serious and non-serious adverse events must be documented in the source records and on 
the respective section of the CRF, regardless of severity or the assumption of a causal 
relationship.  The documentation includes: dates of onset and resolution, severity, seriousness, 
study drug intervention, treatment and outcome, as well as, the causal relationship between the 
event and the study drug in accordance with Section 7.1.4. This documentation is required for 
all AEs that occur: 
a. from the date of signing the informed consent, and 
b. until the off-study date or 90 days after the last administration of study drug, whichever 
is longer, or until a new treatment is initiated (see Section 3.1.10 for subjects who begin 
other anti-cancer treatment). 
 
Immune Related Adverse Events (irAEs) will be collected from the time of informed consent 
through 90 days after the last dose of the last study treatment (regardless of initiation of 
another therapy).  
7.1.6 Expedited Serious Adverse Event (SAE) Reporting Requirements 
In addition to the General Reporting Requirements specified in Section 7.1.5, all events 
meeting the criteria for an SAE per Section 7.1.1, irrespective of suspected causation, must be 
reported by the Investigator to the Sponsor’s Drug Safety Contact (primarily) or, alternatively, 
to the Primary Sponsor Contact, within 24 hours of becoming aware of the event (see contact 
information below). SAEs should be reported via the Medidata RAVE data capture system 
(which utilizes “Safety Gateway”), using the respective Adverse Event and Safety Case 
Summary eCRFs.  This includes any deaths that occur after the off-study date, but within 30 
days of last study drug administration. In the event that the SAE cannot be reported via 
Medidata RAVE, the SAE should be reported using the “Initial Serious Adverse Event Report 
Form,” provided by the Sponsor. 
Note: If an SAE cannot be reported via Medidata RAVE or the “Initial Serious Adverse Event 
Report Form” within 24 hours of becoming aware of the event, the Sponsor’s Drug Safety 
Contact (primarily) or, alternatively, the Primary Sponsor Contact, must be contacted by 
phone or email within 24 hours of becoming aware of the event. In this case, the phone or 
email notification can then be followed up through Medidata RAVE or an “Initial Serious 
Adverse Event Report Form” within one working day of the event. 
If the “Initial Serious Adverse Event Report Form” is being used, the expedited reports should be 
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Sponsor Contact.  Studies utilizing Medidata RAVE (and the “Safety Gateway”), built into the 
eCRF, and respective SAE reporting procedures, do not require reporting by fax or email.  
Questions related to Medidata RAVE and “Safety Gateway” procedures should be directed to 
the Drug Safety Contact or Primary Sponsor Contact (see table below for contact information). 
In urgent cases, pre-notification via phone or informal e-mail should be considered. 
Drug Safety Contact: 
Gary O’Donnell, MS 
Senior Manager, Drug Safety 
Clinical Trials Management 
Ludwig Institute for Cancer Research 
666 3rd Ave, 28th Floor 
New York, New York 10017 
Tel: 
+1 212 450 1551 
Fax: 
+1 212 450 1535 
godonnell@licr.org 
Primary Sponsor Contact: 
Mary Macri 
Director 
Clinical Trials Management 
Ludwig Institute for Cancer Research 
666 3rd Ave, 28th Floor 
New York, New York 10017 
Tel: 
+212 450 1546 
Fax: 
+212 450 1535 
mmacri@licr.org  
 
Serious adverse events must also be reported by the Principal Investigator to the respective 
Institutional Review Board after being assigned an SAE tracking number by the Sponsor.  
Institutional Review Boards may have specific rules on which AEs need to be reported 
expeditiously, as well as, the time frames for such reporting. 
Serious Adverse Event Reports will be evaluated by the Sponsor’s Medical Monitor.  Regulatory 
authorities and other Investigators, as well as institutional and corporate partners, will be 
informed by the Sponsor as required by ICH guidelines, laws and regulations in the countries 
where the investigational agent is being administered.  In particular, SAEs that are unexpected 
and for which a causal relationship with the study drug cannot be ruled out, will be reported by 
the Sponsor within 15 calendar days; if they are life-threatening or fatal, they will be reported 
within 7 Calendar days. 
Serious adverse event reporting to Medimmune/AstraZeneca is described in a separate 
agreement. 
7.1.7 Serious Adverse Event (SAE) Follow-up Requirements 
Subjects experiencing SAEs should be followed closely until the condition resolves or stabilizes, 
and every effort should be made to clarify the underlying cause.  Follow-up information related 
to SAEs must be submitted to the Sponsor as soon as relevant data are available. 
7.1.8 Adverse Events of Special Interest (AESIs) 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to the 
understanding of the investigational products and may require close monitoring and rapid 
communication by the Investigator to the Sponsor. An AESI may be serious or non-serious. The 
rapid recording of all AEs, including AESIs, allows ongoing surveillance of these events in order 
to characterize and understand them in association with the use of the investigational products.   


 
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AESIs for durvalumab and tremelimumab include but are not limited to events with a potential 
inflammatory or immune-mediated mechanism and which may require more frequent 
monitoring and/or interventions such as steroids, immunosuppressants and/or hormone 
replacement therapy. These AESIs are being closely monitored in clinical studies with 
durvalumab monotherapy and combination therapy. An immune-related adverse event (irAE) is 
defined as an adverse event that is associated with drug exposure and is consistent with an 
immune-mediated mechanism of action and where there is no clear alternate aetiology. 
Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be used to support 
an irAE diagnosis. Appropriate efforts should be made to rule out neoplastic, infectious, 
metabolic, toxin, or other etiologic causes of the irAE. 
If the Investigator has any questions in regards to an AE being an irAE, the Investigator should 
promptly contact the Medical Monitor. 
If an AESI also meets SAE criteria, the event will be reported as an SAE per Section 7.1.6. 
AESIs observed with durvalumab and tremelimumab and those considered AESIs for the 
purpose of this study are listed below.  Further information on these AESIs (e.g. presenting 
symptoms) can be found in the current versions of the durvalumab and tremelimumab 
Investigator’s Brochures. Guidelines for the management of subjects experiencing these 
toxicities can be found in Section 8.3.1 and in the following Medimmune guideline: 
“Medimmune’s Dosing Modification and Toxicity Management Guidelines for Immune- 
mediated, Infusion Related, and Non Immune-mediated Reactions (MEDI4736 (durvalumab) 
Monotherapy or Combination therapy with Tremelimumab or Tremelimumab monotherapy).” 
• 
Colitis 
Diarrhea and colitis are the most commonly observed treatment-emergent AEs following 
dosing with study medications.  In rare cases, colon perforation may occur that requires 
surgery (colectomy) or can lead to a fatal outcome, if not properly managed. 
• 
Pneumonitis 
Adverse events of pneumonitis have been observed with anti-PD-1, and anti-PD-L1 
antibodies.(89) Initial work-up should include high-resolution CT scan, ruling out 
infection, and pulse oximetry.  Typically, pulmonary consultation is required. 
• 
Hepatic Function Abnormality (Hepatotoxicty, Hepatitis) 
Increased transaminases have been reported during treatment with anti-PD-L1/anti-PD-
1 antibodies.(89) Inflammatory hepatitis has been reported in 3% to 9% of subjects 
treated with anti-CTLA-4 monoclonal antibodies (e.g., ipilimumab).  The clinical 
manifestations of ipilimumab-treated subjects included general weakness, fatigue, 
nausea and/or mild fever and increased liver function tests such as AST, ALT, alkaline 
phosphatase, and/or total bilirubin. Hepatic function abnormality is defined as any 
increase in ALT or AST to greater than 3 × ULN and concurrent increase in total bilirubin 
to be greater than 2 × ULN.  Concurrent findings are those that derive from a single 
blood draw or from separate blood draws taken within 8 days of each other.  Follow-up 
investigations and inquiries will be initiated promptly by the investigational site to 
determine whether the findings are reproducible and/or whether there is objective 
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cholelithiasis and bile duct obstruction with distended gallbladder) or an agent other 
than the investigational product. Cases where a subject shows an AST or ALT ≥ 3 x ULN 
or total bilirubin ≥ 2 x ULN may need to be reported as SAEs. These cases should be 
reported as SAEs if, after evaluation they meet the criteria for a Hy’s Law case or if any 
of the individual liver test parameters fulfill any of the SAE criteria. 
• 
Neurotoxicity (Neuropathy/Neuromuscular toxicity) 
Immune-mediated nervous system events include encephalitis, peripheral motor and 
sensory neuropathies, Guillain-Barré, and myasthenia gravis.  
• 
Endocrine Disorders 
Immune-mediated endocrinopathies include hypo- and hyper-thyroidism, adrenal 
insufficiency, hypophysitis/hypopituitarism and Type 1 diabetes mellitus. 
Type 1 diabetes mellitus: For subjects with suspected diabetes mellitus, Investigators 
should obtain an endocrinology consult and institute appropriate management which 
may include the administration of insulin. 
• 
Dermatitis/Rash 
Prompt treatment with steroids (topical or systemic based on severity) is important as 
per current established toxicity management guidelines. 
• 
Nephritis and increases in serum creatinine 
A consult with a Nephrologist should be done as well as monitoring for signs and 
symptoms that may be related to changes in renal function (e.g., routine urinalysis, 
elevated serum BUN and creatinine, decreased creatinine clearance, electrolyte 
imbalance, decrease in urine output, proteinuria, etc.). Subjects should be thoroughly 
evaluated to rule out any alternative etiology (e.g., disease progression, infections, etc.). 
Steroids should be considered in the absence of clear alternative etiology even for low 
grade events (Grade 2), in order to prevent potential progression to higher grade event. 
• 
Pancreatic Disorders 
Immune-mediated pancreatitis includes autoimmune pancreatitis (or labs suggestive of 
pancreatitis); increased serum lipase, increased serum amylase) 
• 
Hypersensitivity and Infusion Reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported with 
anti-PD-L1 and anti-PD-1 therapy.(89)  As with the administration of any foreign protein 
and/or other biologic agents, reactions following the infusion of monoclonal antibodies 
(MAbs) can be caused by various mechanisms, including acute anaphylactic (IgE-
mediated) and anaphylactoid reactions against the MAb, and serum sickness.  Acute 
allergic reactions may occur, may be severe, and may result in death.  Acute allergic 
reactions may include hypotension, dyspnea, cyanosis, respiratory failure, urticaria, 
pruritus, angioedema, hypotonia, arthralgia, bronchospasm, wheeze, cough, dizziness, 
fatigue, headache, hypertension, myalgia, vomiting and unresponsiveness. 
 


 
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7.2 Administrative Sponsor Requirements 
7.2.1 Study Master Files 
The Investigator must retain a Sponsor-specified comprehensive and centralized filing system 
(“Study Master File”) of all trial-related documentation that is suitable for inspection by the 
Sponsor and regulatory authorities.  Upon completion of the trial, the Investigator is required to 
submit a summary report to the Sponsor. 
The Investigator must arrange for the retention of the Study Master File for a period of time 
determined by the Sponsor.  No part of the Study Master File shall be destroyed or relocated 
without prior written agreement between the Sponsor and the Investigator. 
7.2.2 Case Report Form Data Collection 
Electronic Case Report Forms (eCRF) will be completed in accordance with respective guidance 
and after training provided by the Sponsor.  The use of eCRFs encompasses electronic data 
entry, query management and sign-off.  Systems used for electronic data capture will be 
compliant with FDA regulations 21 CFR Part 11 and within the constraints of the applicable local 
regulatory agency guidelines (whichever provides the greatest protection to the integrity of the 
data). 
All subjects who sign an informed consent form, regardless of study procedures performed, will 
be assigned a screening number and have their data entered into the eCRF. 
The Investigator will sign and date the completed eCRF sections.  This signature will indicate a 
thorough inspection of the data in the CRF and will certify its content. 
7.2.3 Language 
The protocol is written in English.  All correspondence between the study site and the Sponsor 
should be maintained in English.  Case Report Forms must be completed in English.  All written 
material to be used by subjects and para-clinical staff must use vocabulary that is clearly 
understood, and be in the language appropriate for the trial site. 
7.2.4 Monitoring 
The Sponsor will oversee the conduct of the study and perform clinical monitoring visits for site 
qualification, site initiation, routine monitoring and site close-out.  Clinical Monitors and/or 
other Sponsor staff will meet with the Investigator staff and require direct access to source 
data/documents.  Such access may also be required for Institutional Review Board review, and 
regulatory inspection/audits.  Direct access is defined as permission to examine, analyze, verify, 
and reproduce any records and reports that are important to the evaluation of the study.  All 
reasonable precautions within the constraints of the applicable regulatory requirement(s) to 
maintain the confidentiality of subjects’ identities and Sponsor’s proprietary information will be 
exercised. 
It is the Clinical Monitor’s responsibility to inspect the CRFs at regular intervals throughout the 
trial to verify adherence to the protocol, the completeness, accuracy and consistency of the 
data, and adherence to GCP guidelines.  The Clinical Monitor should have access to subject 


 
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charts, laboratory reports, and other subject records needed to verify the entries on the CRFs 
(“source data verification”). 
7.2.5 Protocol Amendments 
Protocol amendments may be implemented only after approval by the Investigator, Sponsor, 
Institutional Review Board and, if required, the regulatory authorities.  Amendments that are 
intended to eliminate an apparent immediate hazard to subjects may be implemented prior to 
such approvals; however, in this case, approval must be obtained as soon as possible after 
implementation. Implementation of administrative amendments that do not affect the safety of 
the subjects usually do not require prior Institutional Review Board approval, just notification. 
When immediate deviation from the protocol is required to eliminate immediate hazard(s) to 
subjects, the Investigator will contact the Sponsor, if circumstances permit, to discuss the 
planned course of action.  Any departures from the protocol must be fully documented in the 
source documentation. 
7.2.6 Premature Subject Withdrawal from Treatment or from Study 
A subject may withdraw from study treatment or from the study at any time for any reason 
without prejudice to his/her future medical care by the physician or at the study site.  Likewise, 
the Investigator and/or Sponsor have the right to withdraw subjects from treatment or from the 
study.  Specific subject withdrawal criteria are listed in Section 3.1.10.  Should a subject (or a 
subject’s legally authorized representative) decide to withdraw from study treatment or from 
the study, all efforts will be made to complete the required study procedures and report the 
treatment observations as thoroughly as possible. 
For all subject withdrawals, a complete final evaluation should be made at the time of 
withdrawal.  The appropriate form in the Case Report Form should be completed with an 
explanation of why the subject is withdrawing, and an attempt should be made to perform a 
follow-up evaluation. 
7.2.7 Early Trial Termination 
The Study Sponsor and Investigator have the right to terminate the study early.  Specific study 
stopping rules are listed in Section 3.1.14 (Safety Monitoring and Study Stopping Rules).  In such 
case, one party must notify the other in advance in writing about the intent of and the reasons 
for the termination.  The Investigator must also notify the appropriate Institutional Review 
Board accordingly. 
7.2.8 Study Drug Shipments and Accountability 
Study drug shipments will be addressed to the Principal Investigator’s authorized designee, 
preferably, the site’s pharmacy.  The recipient will verify the amount and condition of the drug 
and will return a signed Acknowledgment of Receipt to the shipper. 
A drug dispensing log (inventory) will be kept by the study site, containing at least the following: 
• 
the subject’s identification (subject number and code) 
• 
date and quantity of drug dispensed 


 
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• 
date and quantity of drug returned to the Investigator/pharmacy (if applicable) 
• 
date and quantity of accidental loss of drug (if any)  
These inventories must be made available for inspection by the Clinical Monitor.  The 
Investigator is responsible for seeing to it that all used and unused trial supplies are accounted 
for.  At the end of the study, the Clinical Monitor will also collect the original study drug 
dispensing records. 
 
At the end of the study, or as directed by the Sponsor, all used and unused supplies, including 
partially used or empty containers, will be disposed of or transferred as instructed by the 
Sponsor, and in accordance with local written procedures, if applicable.  Any disposal or transfer 
of investigational agent shall be noted on the investigational drug disposition log and signed by a 
second person.  At the end of the study, the Clinical Monitor will collect the original drug 
disposition logs. 
7.3 Regulatory, Legal and Ethical Requirements 
7.3.1 Good Clinical Practice (GCP), Laws and Regulations 
The Investigator must ensure that he/she and all authorized personnel for the study are familiar 
with the principles of Good Clinical Practice (GCP) and that the study is conducted in full 
conformity with the current revision of the Declaration of Helsinki, ICH Guidelines, and 
applicable local laws and regulations, with the understanding that local laws and regulations 
take precedence over respective sections in the Declaration of Helsinki and/or the ICH 
Guidelines. 
7.3.2 Informed Consent 
The Investigator must obtain witnessed (if applicable) written Informed Consent from the 
subject or the subject’s legally authorized representative after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any study 
procedures are performed.  The subject should be given a copy of the Informed Consent 
documentation.  The original signed and dated Informed Consent form must be retained in the 
study records at the study site, and is subject to inspection by representatives of the Sponsor, or 
representatives from regulatory agencies. 
7.3.3 Institutional Review Board 
The Investigator must obtain written approval from the appropriate Institutional Review Board 
for the protocol and Informed Consent, and all amendments thereof, prior to recruitment of 
subjects and prior to shipment of investigational agents. 
The Investigator must report SAEs to the appropriate Institutional Review Board in accordance 
with the Institutional Review Board’s rules and guidelines (see also Section 7.1). 
The Investigator must assure that continuing review (at least once per year) of the study is 
performed by the Institutional Review Board throughout the duration of the study.  If so 
required by the Institutional Review Board, the Investigator must provide study reports on an 
annual basis and upon completion of the study. 


 
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All correspondence with, and reports to, the Institutional Review Board must be maintained in 
the study files at the study site and copies must be sent to the Sponsor. 
7.3.4 Subject Confidentiality 
The Investigator must ensure that the subject’s privacy is maintained.  A subject should only be 
identified by their initials, date of birth and subject number on the CRFs or other documents 
submitted to the Sponsor.  Documents that are not submitted to the Sponsor (e.g., signed 
Informed Consent form) should be kept in a strictly confidential section of the study file by the 
Investigator. 
The Investigator shall permit the Sponsor and authorized representatives of regulatory agencies 
to review the portion of the subject’s medical record that is directly related to the study.  As 
part of the Informed Consent process, the subject must have given written consent that his/her 
records will be reviewed in this manner. 
 


 
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8 
Appendices 
8.1 Protocol Version History 
Original Issue 
Issue date: 17-DEC-2015 
Summary of Changes: not applicable 
 
Amendment 001 
Issue date: 16-FEB-2016 
Summary of Changes: 
1. Synopsis, Section 3.2, Section 4: sample collections and assessments were removed for 
PK (durvalumab and tremelimumab) ADA (durvalumab and tremelimumab) and sPD-L1.   
2. Section 3.1.7, next to last paragraph: ±4 days was added to Day 128 and Day 156. 
3. Section 3.1.16: The following was added: “The first Post Study Follow-up will include a 
query to determine if there were any immune-related adverse events (irAEs) since the 
last study visit.  If the first Post Study Follow-up is less than 90 days since the last 
administration of study drug, any irAEs occurring since the last study visit will continued 
to be collected and be recorded at the subsequent Post Study Follow-up visit.” 
4. Section 3.2:  
a. Deleted footnote 5 and re-numbered footnote 9 to footnote 5. This was done 
due to removal of PK from flowchart. 
b. Amylase and lipase assessments were added to flowchart 
c. Study Flowchart for Cohorts 2 and 4: coagulation and urinalysis were added to 
On Study Follow-up. 
5. Sections 4.2 (PK), 4.3 (Immunogenicity) and 4.5.1.1 (sPD-L1) were deleted, and other 
sections were re-numbered as appropriate. 
6. Section 7.1.7: The phrase “using the “SAE Follow-up Report form”, provided by the 
Sponsor” was deleted; directions are provided in the previous section. 
7. Section 8.3.1:  
a. Deleted paragraph, which referenced the package inserts for ipilimumab, 
nivolumab, and pembrolizumab. 
b. MED4736 was changed to durvalumab in the table. 
8. General spelling, capitalization, grammatical and formatting changes were implemented, 
as needed. 
 
Amendment 002 
Issue date: 16-MAR-2016 
Summary of Changes: 
 
1. Synopsis, Section 3.1, Section 3.1.7, Table 3, Figures 1-4 and Section 3.2, Flowchart: 
Added doses for durvalumab (1500 mg), tremelimumab (75 mg) 
2. Synopsis, Section 3.1.7, Figures 1-4, and Section 3.2: added dose regimen for HDT - 
melphalan (200 mg/m2 IV); first occurrence was defined as melphalan 200 mg/m2 IV 
according to institution practice. 
3. Section 3.1.9:  the following changes were made to the DLT criteria: 


 
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a. Grade 3 toxicity: the exceptions for “rash,” “pneumonitis,” and “increase in AST, 
ALT, bilirubin, and alkaline phosphatase” were deleted. 
b. “Isolated Grade 3 electrolyte abnormalities (i.e., those occurring without clinical 
consequence), except those that resolve, with or without intervention, to <Grade 
2 within 72 hours” was added 
c. “Grade 5 toxicity, treatment-related death” was added. 
4. Section 3.1.14, #4: removed the phrase “assessed as related to durvalumab, 
tremelimumab, and/or PBL reinfusion.” 
5. Section 3.1.16: the 5th paragraph was changed FROM: “The first Post Study Follow-up will 
include a query to determine if there were any immune-related adverse events (irAEs) 
since the last study visit.  If the first Post Study Follow-up is less than 90 days since the 
last administration of study drug, any irAEs occurring since the last study visit will 
continued to be collected and be recorded at the subsequent Post Study Follow-up visit.”  
TO: The Post Study Follow-up will include a query to determine if there were any 
immune-related adverse events (irAEs) during the 90 days since the last administration 
of study drug.” 
6. Section 3.2: 
a. The following was added to blood hematology blood sample: “…..& other 
parameters as clinically indicated; e.g., reticulocytes, blasts, etc.”  
b. Footnote 9 was added: “Standard of Care procedures may be used for eligibility 
assessments provided they meet the criteria specified in either the inclusion 
criteria or flowchart.” 
c. Concomitant procedures was added to Concomitant medications line. 
d. “x’ was removed from PFS line at first On Study Follow-up, as it was a misplaced 
mark. 
7. Section 5, Subject Eligibility: The following note was added: “Note: Standard of Care 
procedures may be used for eligibility assessments provided they meet the criteria 
specified in either the inclusion criteria or flowchart.” 
8. Section 5.3.1: Added the following to non-permitted concomitant therapies: “Drugs with 
laxative properties and herbal or natural remedies for constipation should be avoided 
through 90 days post last dose of tremelimumab because of the potential for 
exacerbation of diarrhea.” 
9. Section 7.2.2: the following statement was added: “All subjects who sign an informed 
consent form, regardless of study procedures performed, will be assigned a screening 
number and have their data entered into the eCRF.” 
10. Section 8.3.1: Durvalumab and tremelimumab dose modifications for all other AEs (last 
portion of table) was changed as follows: 
a. Grade 3 was separated from Grade 2 modifications 
b. Grade 3 modifications were added:  "Hold D and T. If AEs downgrade to ≤ Grade 
2 within 7 days or resolve to ≤ Grade 1 or baseline within 14 days, resume D and 
T administration at next scheduled dose. Otherwise, discontinue D and T 
permanently.” 
c. Grade 4, bullet 2: the phrase ”in consultation with the Sponsor” was added 
11. Section 8.3.2:  
a. For Point 2, “7 days or less” was changed to “≤ half the planned dosing interval.” 
b. For Point 3, “7 days“ was changed to “half the planned dosing interval.” 


 
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12. Administrative:  
a. Spelling, grammar and typographical errors were corrected; formatting changes 
were implemented, as applicable. 
b. Monitor and Study Monitor were standardized as “Clinical Monitor” in Sections 
7.2.4 and 7.2.8. 
c. List of abbreviations was updated 
 
Amendment 3 
Issue date: 28-MAR-2017 
Summary of Changes: 
 
1. Section 2 (Study Rationale): the following paragraph was added based on clarification 
provided by Medimmune/AstraZeneca: ”Fixed dosing for durvalumab is recommended 
only for subjects with > 30kg body weight due to endotoxin exposure.  Subjects with a 
body weight ≤ 30 kg are not eligible for enrollment in the current study.  If a subject’s 
body weight drops to ≤ 30 kg while on the study, the subject will be dosed according to 
the details provided in Section 6.1.” 
2. Section 3.1.7 (Treatment Cohorts): the following paragraph was added: “Note for 
durvalumab fixed dosing: The durvalumab fixed dosing is for subjects who weigh > 30 
kg.  If a subject’s body weight drops to ≤ 30 kg while on the study, the subject will be 
dosed at 600 mg for durvalumab as long as the body weight remains ≤ 30 kg.” 
3. Section 3.1.9 (DLT and MTD/RCD). #1 was changed to clarify the need for 3 consecutive 
assessments (changes in bold): “Delayed engraftment: Neutrophil engraftment will be 
defined as the first of 3 consecutive days assessments with absolute neutrophil count 
>500/mm3.  Platelet engraftment will be defined as the first of 3 consecutive days 
assessments of platelets >20,000/mm3 without platelet transfusion in the prior 7 
days.  Engraftment will be considered delayed (and therefore a DLT) if the subject has 
not met criteria for both neutrophil and platelet engraftment by Day 30 after ASCT. 
4. Section 3.1.10 (Subject Withdrawal from Treatment/Study):  For the “withdrawn from 
study” category, # 2 was clarified (changes in bold): “Initiation of alternative anticancer 
therapy including another (marketed or investigational agent). 
5. Sections 3.1.11 (Subject Evaluability and Replacement) and 4.1.2 (Subject Evaluation and 
Statistics) were re-organized to clarify the per-protocol population for DLT evaluation. 


 
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a. Section 3.11 was changed FROM: “Subjects are fully evaluable for DLT if: (1) They 
experience a DLT at any time during the DLT Evaluation Period (as defined in 
Section 3.1.9), or (2) In the absence of a DLT, they receive at least 75% of the 
total dose of each study drug, receive all associated transplant procedures per 
standard of care, and undergo respective safety assessments, without major 
protocol violations, over the entire DLT evaluation period. Subjects who are not 
fully evaluable for DLT will be replaced.”  TO: “Subjects are fully evaluable for 
DLT if they fulfill the criteria for the Per-Protocol Population for DLT Assessment 
(as defined in Section 4.1.2). Subjects who are not fully evaluable for DLT per 
Section 4.1.2 will be replaced.” 
b. Section 4.1.2 was changed FROM: “See Section 3.1.11 for subject evaluability 
and replacement for DLT assessments. In addition, all subjects who receive at 
least 1 dose of durvalumab or tremelimumab will be assessed for overall safety 
and tolerability.” TO: “The Per-Protocol (PP) Population for DLT Assessment 
includes: (1) All subjects who experience a DLT at any time during the DLT 
Evaluation Period (as defined in Section 3.1.9); (2) All subjects with no DLT who 
receive at least 75% of the scheduled doses of durvalumab and tremelimumab 
(according to the respective cohort requirements), receive all associated 
transplant procedures per standard of care, and undergo respective safety 
assessments without major protocol violations over the entire DLT Evaluation 
Period (as defined in Section 3.1.9)  
See Section 3.1.11 for subject evaluability and replacement for DLT assessments. 
The Safety Population is defined as all subjects who receive at least 1 dose of 
durvalumab or tremelimumab. The overall analysis of safety and tolerability will 
be based on the Safety Population. 
c. Section 4.1.2:  The following paragraph was added: “For each continuous 
laboratory parameter, results will be categorized as low, normal, or high based 
on the laboratory normal ranges. Frequencies and percentages will be presented 
for the shifts in these categories (i.e., low to normal, low to high, high to low, 
etc.) from baseline to each post-treatment assessment time point. Additionally, 
for each continuous hematology and chemistry parameter, descriptive statistics 
will be presented for the changes from baseline to each post-treatment 
assessment time point. Descriptive statistics will be presented for the changes in 
vital signs from baseline to each post-treatment assessment time point.”  
6. Section 3.1.14 (Safety Monitoring and Study Stopping Rules): Removed Celgene from 
Safety Review, as Celgene is not involved in this review. 
7. Section 3.1.16 (On Study and Post Follow-up): 3rd paragraph was changed (changes in 
bold): “If the determination is made to remove a subject from treatment at a visit that 
coincides with the first visit of the On Study Follow-up Period (which is 28 days after the 
last dose of study treatment), any assessments required in the 28 day post-last 
treatment first On Study Follow-up visit that are not covered as part of the last on-
treatment visit (usually correlative labs) should be done as soon as possible.  If these 
assessments cannot be done on the same day, the subject should be brought back in at 
the earliest opportunity.  Any assessments or correlative samples required by both the 
protocol last on-treatment visit and the 28 day post-last treatment first On Study 
Follow-up visit should not be repeated. 


 
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8. Section 3.1.16.1 (End of study Visit): section was added. 
9. Section 3.2 (Flowchart): 
a. Added ECOG PS to On Study Follow up +56 and +91 to align with physical exams. 
b. Deleted pre-existing conditions from medical history line; this is consistent with 
current protocols. 
c. Added Mg to chemistry analytes; it was previously inadvertently omitted. 
d. Added beta-2 microglobulin to myeloma serum tests 
e. Added “24-hr as applicable” to myeloma urine tests; deleted N-telopeptide as it 
is no longer assayed. 
f. For Cohorts 2 and 4, moved FDG/PET assessment and Bone Marrow samples 
from first On Study Follow-up to Second On Study Follow-up visit; this was done 
in order to align the 1-year measurements uniformly at approximately Day 324 
post ASCT for Cohorts 1/3 and Cohorts 2/4. 
g. Added the following note to Footnote 3 “Note: It is strongly recommended that 
hematology, chemistry and pregnancy test (when applicable) results are 
reviewed before dosing.” 
h. Added Footnote 10: “See section 7.1.5 for details regarding collection of AEs for 
90 days after last study drug administration.” 
10. Section 4.2.1.4 (PFS):  The first sentence was clarified (changes in bold): “One-year PFS 
(Day 324 ± 4 days) will be determined for each subject.  
11. Section 5.1 (Inclusion Criteria):  
a. #2 was clarified (changes in bold): “Measurable disease either at enrollment, 
prior to most recent line of salvage therapy, or prior to most recent line of 
induction therapy. Measurable disease as is defined by any of the following:” 
b. #13 was added based on updated requirements from Medimmune/ AstraZeneca: 
“Body weight > 30 kg.” 
12. Section 5.2 (Exclusion Criteria): 
a. #17, Contraception information, was updated based on current 
recommendations from Medimmune/ AstraZeneca. 
b. #19, blood donation restriction, was added based on recommendation from 
Medimmune/AstraZeneca. 
13. Section 5.3.2 (Permitted Concomitant Therapies), last sentence was corrected per 
current standard language (changes in bold): “All non-drug therapies must be recorded in 
the respective sections of the Case Report Form or as adverse events. 
14. Section 6 (Study Drug Administration), second sentence was updated per current 
standard language (changes in bold): “On the days when durvalumab and tremelimumab 
are to be administered together, durvalumab infusion will start at least 60 ±5 minutes 
after the end of tremelimumab infusion. 
15. Sections 6.1 (Durvalumab) and 6.2 (Tremelimumab): 
a. Entire sections were reorganized and re-written per current Medimmune/ 
AstraZeneca standard language 
b. Weight restriction for fixed dosing was added (for durvalumab only) 
c. 5% dextrose was added as an alternate diluent 
d. Requirement for an infusion pump was removed 
16. Section 6.5 (Monitoring of tremelimumab and durvalumab dose administration). The 
following note was added: “Note: When durvalumab and tremelimumab are to be 


 
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administered on the same day, durvalumab infusion will start at least 60 minutes after 
the end of tremelimumab infusion even though vital signs assessment is not required 
during the entire 60 minute period post tremelimumab.” 
17. Section 7.1.2 (Additional Expedited Reporting Requirements for This Study). Paragraph 1 
was changed per current standard protocol language FROM: ” For the purpose of this 
study, the following events are considered medically important conditions and must be 
reported in an expedited manner (see Section 7.1.6 for Sponsor contact information:” 
TO: “For the purpose of this study, the following events must be reported by phone or 
email to the Sponsor within 24 hours of knowledge of the event (see Section 7.1.6 for 
Sponsor contact information) and may result in submission of an SAE based on certain 
criteria outlined below:” 
18. Section 7.1.2.1.1 (Maternal Exposure). The follow paragraph was added: “Female 
subjects should avoid becoming pregnant and breastfeeding during the study and for 
90 days after the last dose of durvalumab or for 6 months after the last dose of 
tremelimumab (whichever is longer).” 
19. Section 7.1.2.1.2 ((paternal Exposure).  The first paragraph was updated to current 
standard language (changes in bold): “Male subjects should refrain from fathering a child 
or donating sperm during the study and for 6 months after the final dose of 
investigational product 90 days after the last dose of durvalumab or for 6 months after 
the last dose of tremelimumab (whichever is longer).  
20. Section 7.1.5 (General Reporting Requirements) was re-written per current standard 
language; changed FROM: “Documentation of serious and non-serious AEs includes: 
dates of onset and resolution, severity, seriousness, study drug intervention, treatment 
and outcome, as well as, the causal relationship between the event and the study drug in 
accordance with Section 7.1.4. All serious and non-serious AEs occurring between the 
date of signing the informed consent and the off-study date must be documented in the 
source records and on the respective section of the CRF, regardless of the assumption of 
a causal relationship. During the On Study Follow-up period, all AEs will continue to be 
documented for 90 days after the last dose of study drug.” TO: “All serious and non-
serious adverse events must be documented in the source records and on the respective 
section of the CRF, regardless of severity or the assumption of a causal relationship.  The 
documentation includes: dates of onset and resolution, severity, seriousness, study drug 
intervention, treatment and outcome, as well as, the causal relationship between the 
event and the study drug in accordance with Section 7.1.4. This documentation is 
required for all AEs that occur: (a) from the date of signing the informed consent, and (b) 
until the off-study date or 90 days after the last administration of study drug, whichever 
is longer, or until a new treatment is initiated (see Section 3.1.10 for subjects who begin 
other anti-cancer treatment). Immune Related Adverse Events (irAEs) will be collected 
from the time of informed consent through 90 days after the last dose of the last study 
treatment (regardless of initiation of another therapy).” 
21. Section 7.1.6 (Expedited SAE Reporting Requirements): 
a. Primary Sponsor Contact was changed from Choon-Soo Rim to Mary Macri 
b. The following statement was added: “Serious adverse event reporting to 
Medimmune/AstraZeneca is described in a separate agreement.” 
22. Section 7.1.8 (AESI):  additional details were added for the AESIs per current 
recommendations from Medimmune/AstraZeneca. 


 
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23. Section 8.2 (Participating Study Sites, etc). The following details were added:  
Participating Study Sites: 
• 
Memorial Sloan Kettering Cancer Center, New York, NY 
• 
Mount Sinai Medical Center, New York, NY 
24. Section 8.3.1 (Durvalumab and Tremelimumab Dose Modification Due to Toxicity).  
Updates were made based on current recommendations from Medimmune/AstraZeneca 
(19Aug2016).  
25. Section 8.3.2 (Durvalumab and Tremelimumab Dose Modification Not Due to Treatment-
related Toxicities). Section was changed per current standard language FROM: 
“Durvalumab and tremelimumab administration may be modified or discontinued as a 
result of events other than toxicity, e.g., intercurrent illness or logistical/administrative 
reasons, whereby the following rules should apply: (1) If the subject misses 2 consecutive 
planned doses, the subject should be discontinued from treatment. (2) If the dosing 
interruption is ≤ half the planned dosing interval, the originally planned drug 
administration should be given.  The respective protocol deviation should be 
documented. (3) If the dosing interruption is greater than half the planned dosing 
interval, the dosing should be skipped and the next scheduled drug administration 
should be performed.  The respective protocol deviation should be documented. (4) See 
Section 3.1.7 for details on handling subjects in Cohorts 2 or 4 if Day 30 administration of 
study drug is delayed for >10 days due to extended recovery from transplant related 
toxicities. TO: “Durvalumab and tremelimumab administration may be modified or 
discontinued as a result of events other than toxicity, e.g., intercurrent illness or 
logistical/administrative reasons, whereby the following rules should apply: (1) The 
originally planned visit/treatment schedule should be maintained in general, i.e., dosing 
interruptions should not reset the original treatment schedule. Exceptions may be made 
only for individual dosing days, whereby the interval between any two doses shall be no 
less than 21 days. All resulting protocol deviations should be documented. (2) If the 
dosing interruption causes 2 consecutive planned doses to be missed, the treatment 
should be discontinued. (3) If the dosing interruption is ≤ half the planned dosing 
interval, the originally planned dose should be given and the next dose(s) should be 
adjusted in accordance with #1, if necessary. (4) If the dosing interruption is greater than 
half the planned dosing interval, the dose should be skipped and the next dose(s) should 
be adjusted in accordance with #1, if necessary. (5) See Section 3.1.7 for details on 
handling subjects in Cohorts 2 or 4 if Day 30 administration of study drug is delayed for 
>10 days due to extended recovery from transplant related toxicities.   
26. Administrative:  
a. Spelling, grammar and typographical errors were corrected; formatting changes 
were implemented, as applicable. 
b. List of abbreviations was updated 
 
 
 


 
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8.2 Participating Study Sites, Investigators and Staff, Laboratories, and 
Sponsor Information 
Participating Study Sites: 
• 
Memorial Sloan Kettering Cancer Center, New York, NY 
• 
Mount Sinai Medical Center, New York, NY 
Additional information is maintained in the Clinical Study File 
 
 


 
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8.3 Dose Adjustments and Delays for Durvalumab and Tremelimumab 
8.3.1 Durvalumab and Tremelimumab Dose Modification Due to Toxicity 
Durvalumab (MEDI4736) and tremelimumab administration may be modified or discontinued as 
a result of toxicities as described in the table below.  
Additional information and guidance regarding dose modification due to toxicity are provided 
from MedImmune in the following guideline: “MedImmune’s Dosing Modification and Toxicity 
Management Guidelines for Immune-mediated, Infusion Related, and Non Immune-mediated 
Reactions (MEDI4736 Monotherapy or Combination therapy with Tremelimumab or 
Tremelimumab monotherapy).” 
Dose modifications will not be required for AEs that are clearly not attributed to durvalumab or 
tremelimumab (such as an accident) or for laboratory abnormalities that are not deemed to be 
clinically significant. 
Durvalumab (D) and Tremelimumab (T) Dose Modification Due to Toxicity 
Note: If D and T dosing is held temporarily until resolution of the event as per instructions below, 
treatment should resume at the next scheduled treatment date. 
Immune-related Adverse Events (irAEs) 
Immune-related adverse events are defined as AEs of immune nature (i.e., inflammatory) in the 
absence of a clear alternative etiology.  Maximum supportive care, including immunosuppressive 
medications, such as high dose steroids, is allowed to induce resolution of the event.  However, 
infliximab should not be used for management of immune-related hepatitis. 
In addition to the criteria for permanent discontinuation of D and T depicted below, permanently 
discontinue D and T also for:  
• Any Grade rash with bullous skin formations. 
• Inability to reduce corticosteroid to a dose of ≤10 mg of prednisone per day (or equivalent) 
within 12 weeks after last dose of study drug/regimen. 
• Recurrence of a previously experienced Grade 3 treatment-related AE following resumption of 
dosing. 
Grade 1 
• 
In general, no dose modification required. 
• 
For pneumonitis/interstitial lung disease, consider holding D and T dosing as clinically appropriate 
and during diagnostic work-up for other etiologies. 
Grade 2 
• 
In general, hold D and T until resolution to ≤ Grade 1 and after the end of any steroid taper, and 
discontinue D and T permanently if such resolution does not occur within 60 days (30 days for 
neurotoxicities).  Criteria for temporary hold or permanent discontinuation of D and T may differ 
by event as detailed below. 
• 
For pneumonitis/interstitial lung disease, the decision to reinitiate D and T upon resolution shall be 
based upon treating physician’s clinical judgment (as long as the event does not meet DLT criteria). 


 
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Durvalumab (D) and Tremelimumab (T) Dose Modification Due to Toxicity 
• 
For peripheral neuromotor syndromes, such as Guillain-Barre and Myasthenia Gravis, follow 
general instructions above, but always discontinue D and T permanently if there are signs of 
respiratory insufficiency or autonomic instability. 
• 
For endocrinopathies, other than isolated hypothyroidism, follow general instructions above, but 
subjects may be retreated if the endocrinopathy is controlled and the subject is clinically stable 
while requiring steroid doses of ≤ 10 mg/day prednisone equivalent. 
• 
For isolated hypothyroidism managed with hormone replacement therapy, and for sensory 
neuropathy/neuropathic pain, holding D and T is at the discretion of the investigator. 
• 
For elevated creatinine or rash, D and T should be held until resolution to ≤ Grade 1 or baseline. 
• 
For vitiligo, no dose modification required. 
Grade 3 
• 
In general, hold D and T until resolution to ≤ Grade 1, and after the end of any steroid taper, and 
discontinue D and T permanently if such resolution does not occur within 60 days (30 days for 
neurotoxicities and rash).  Criteria for permanent discontinuation of D and T may differ by event as 
detailed below. 
• 
For peripheral neuromotor syndromes (such as Guillain-Barre and Myasthenia Gravis), apply 
respective Grade 2 rules. 
• 
For endocrinopathies, follow Grade 2 instructions above. 
• 
For pneumonitis/interstitial lung disease, diarrhea/enterocolitis and elevated serum creatinine 
(e.g., nephritis or renal dysfunction), always discontinue D and T permanently. 
• 
For asymptomatic increases of amylase or lipase levels, hold D and T, and if complete work up 
shows no evidence of pancreatitis, D and T may be continued. 
• 
For hepatitis, discontinue D and T permanently for (1) transaminases or bilirubin not resolving to ≤ 
Grade 1 or baseline within 14 days, (2) transaminases > 8 × the upper limit of normal (ULN) or 
bilirubin > 5 × ULN, or (3) any case meeting Hy’s law criteria (as defined in FDA Guidance Document 
“Drug-Induced Liver Injury”). 
• 
For rash, M and T should be held until resolution to ≤ Grade 1 or baseline. 
Grade 4 
• 
In general, discontinue D and T permanently. 
• 
For endocrinopathies, follow Grade 2 instructions above. 
• 
For asymptomatic increases of amylase or lipase levels, hold D and T, and if complete work up 
shows no evidence of pancreatitis, D and T may be continued.  


 
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Durvalumab (D) and Tremelimumab (T) Dose Modification Due to Toxicity 
Infusion-related Reactions 
Grade 1 
• 
The infusion rate of D and T may be decreased 50% or temporarily interrupted until resolution of 
the event; total infusion time not to exceed 4 hours. 
• 
Acetaminophen and/or antihistamines may be administered per institutional standards at the 
discretion of the Investigator. 
• 
Premedication for subsequent doses should be considered. 
• 
Steroids should not be used for routine premedication of ≤Grade 2 infusion reactions. 
Grade 2: 
• 
Same as Grade 1, but consider giving subsequent infusions at 50% of the initial infusion rate; total 
infusion time not to exceed 4 hours. 
Grade 3 and 4: 
• 
The infusion must be stopped immediately and treatment permanently discontinued. 
• 
Manage severe infusion-related reactions per institutional standards (e.g., IM epinephrine, 
followed by IV diphenhydramine and ranitidine, and IV glucocorticoid). 
All other Adverse Events 
Grade 1 
• 
No dose modification required. 
Grade 2  
• 
Hold D and T until resolution to ≤ Grade 1 or baseline, and discontinue D and T permanently if such 
resolution does not occur within 60 days. 
Grade 3 
• 
Hold D and T. If AEs downgrade to ≤ Grade 2 within 7 days or resolve to ≤ Grade 1 or baseline 
within 14 days, resume D and T administration at next scheduled dose. Otherwise, discontinue D 
and T permanently. 
Grade 4 
• 
In general, discontinue D and T permanently. 
• 
For isolated lab results, decision to discontinue should be based on accompanying clinical 
signs/symptoms and per Investigator’s clinical judgment in consultation with the Sponsor. 
 
8.3.2 Durvalumab and Tremelimumab Dose Modification Not Due to Treatment-
related Toxicities 
Durvalumab and tremelimumab administration may be modified or discontinued as a result of 
events other than toxicity, e.g., intercurrent illness or logistical/administrative reasons, whereby 
the following rules should apply: 
(1) The originally planned visit/treatment schedule should be maintained in general, i.e., 
dosing interruptions should not reset the original treatment schedule. Exceptions may 
be made only for individual dosing days, whereby the interval between any two doses 
shall be no less than 21 days. All resulting protocol deviations should be documented. 


 
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(2) If the dosing interruption causes 2 consecutive planned doses to be missed, the 
treatment should be discontinued. 
(3) If the dosing interruption is ≤ half the planned dosing interval, the originally planned 
dose should be given and the next dose(s) should be adjusted in accordance with #1, if 
necessary. 
(4) If the dosing interruption is greater than half the planned dosing interval, the dose 
should be skipped and the next dose(s) should be adjusted in accordance with #1, if 
necessary   
(5) See Section 3.1.7 for details on handling subjects in Cohorts 2 or 4 if Day 30 
administration of study drug is delayed for >10 days due to extended recovery from 
transplant related toxicities.   
. 
 


 
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8.4 International Myeloma Working Group (IMWG) Criteria for 
Multiple Myeloma  
References: (87, 88) 
Table A1.1. IMWG Uniform Response Criteria 
Response Category 
Response criteriaa 
sCR 
CR as defined below plus: 
normal FLC ratio and absence of clonal cells in bone marrowb by 
immunohistochemistry or immunofluorescencec 
CR 
Negative immunofixation on the serum and urine and disappearance of any soft 
tissue plasmacytomas and <5% plasma cells in bone marrowb 
VGPR 
Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis OR  
≥ 90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 h 
PR 
≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by 
≥90% or to <200mg per 24 h. 
If the serum and urine M-protein are unmeasurable, a ≥50% decrease in the 
difference between involved and uninvolved FLC levels is required in place of the 
M-protein criteria d 
If serum and urine M-protein are unmeasurable, and serum free light assay is 
also unmeasurable, ≥50% reduction in plasma cells is required in place of M-
protein, provided baseline bone marrow plasma cell percentage was ≥30%  
In addition to the above listed criteria, if present at baseline, a ≥50% reduction in 
the size of soft tissue plasmacytomas is also required 
SD (not recommended for 
use as an indicator of 
response; stability of 
disease is best described by 
providing the time to 
progression estimates) 
Not meeting criteria for CR, VGPR, PR, or progressive disease 
Abbreviations: CR, complete response; FLC, free light chain; PR, partial response; SD, stable disease; sCR, 
stringent complete response; VGPR, very good partial response. 
a - All response categories require two consecutive assessments made at any time before the institution of any 
new therapy; all categories also require no known evidence of progressive or new bone lesions if radiographic 
studies were performed. Radiographic studies are not required to satisfy these response requirements. 
b - Confirmation with repeat bone marrow biopsy not needed. 
c - Presence/absence of clonal cells is based upon the kappa/lambda ratio. An abnormal kappa/lambda ratio by 
immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. An 
abnormal ratio reflecting presence of an abnormal clone is kappa/lambda of >4:1 or <1:2. 
d - Refer to Table A1.3 for definitions of measurable disease. 
 
 


 
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Table A1.2. IMWG Disease Progression and Relapse Definitions 
Relapse Category 
Relapse criteria 
Progressive diseasea 
To be used for calculation of time 
to progression and progression-
free survival end points for all 
subjects including those in CR 
(includes primary progressive 
disease and disease progression 
on or off therapy) 
Progressive Disease: requires any one or more of the following: 
Increase of ≥25% from baseline in: 
1. Serum M-component and/or (the absolute increase must be ≥0.5 
g/dL)b  
2. Urine M-component and/or (the absolute increase must be ≥ 
200 mg/24 h)  
3. Only in subjects without measurable serum and urine M-protein 
levels: the difference between involved and uninvolved FLC levels. 
The absolute increase must be >10 mg/dL.  
4. Bone marrow plasma cell percentage: the absolute % must be ≥10%c  
5. Definite development of new bone lesions or soft tissue 
plasmacytomas or definite increase in the size of existing bone 
lesions or soft tissue plasmacytomas  
6. Development of hypercalcemia (corrected serum calcium >11.5 
mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma 
cell proliferative disorder 
Clinical relapsea 
Clinical relapse requires one or more of:  
Direct indicators of increasing disease and/or end organ dysfunction (CRAB 
features)b It is not used in calculation of time to progression or 
progression-free survival but is listed here as something that can be 
reported optionally or for use in clinical practice 
1. Development of new soft tissue plasmacytomas or bone lesions 
2. Definite increase in the size of existing plasmacytomas or bone 
lesions. A definite increase is defined as a 50% (and at least 1 cm) 
increase as measured serially by the sum of the products of the 
cross-diameters of the measurable lesion 
3. Hypercalcemia (>11.5 mg/dL) [2.65 mmol/L]  
4. Decrease in hemoglobin of ≥2 g/dL [1.25 mmol/L]  
5. Rise in serum creatinine by 2 mg/dL or more [177 µmol/L or 
more]  
Relapse from CRa 
(To be used only if the end point 
studied is DFS)d  
Any one or more of the following: 
1. Development of ≥5% plasma cells in the bone marrowc  
2. Reappearance of serum or urine M-protein by immunofixation or 
electrophoresis  
3. Appearance of any other sign of progression (i.e., new 
plasmacytoma, lytic bone lesion, or hypercalcemia) 
Abbreviations: CR, complete response; DFS, disease-free survival. 
a - All relapse categories require two consecutive assessments made at any time before classification as relapse 
or disease progression and/or the institution of any new therapy. 
b - For progressive disease, serum M-component increases of ≥1 g/dL are sufficient to define relapse if starting 
M-component is ≥5 g/dL. 
c - Relapse from CR has the 5% cutoff versus 10% for other categories of relapse. 


 
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d -For purposes of calculating time to progression and progression-free survival, CR subjects should also be 
evaluated using criteria listed above for progressive disease. 
 
Table A.1.3. IMWG Definitions of Measurable Disease 
Response criteria for all categories and subcategories of response except CR are applicable only to subjects who 
have ‘measurable’ disease as defined in Section 5.1.  
Response criteria for CR are applicable for subjects who have abnormalities on one of the three measurements. 
Note that subjects who do not meet any of the criteria for measurable disease can only be assessed for 
stringent CR, and cannot be assessed for any of the other response categories 
 
 
 


 
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8.5 Laboratory Procedures 
Please refer to the Study Laboratory Manual for information on testing to be done and 
instructions on specimen handling and logistics. 


 
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8.6 ECOG Performance Status  
Eastern Cooperative Oncology Group Performance Status   
Grade 
ECOG PS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
Reference: (90) 
 
 


 
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8.7 List of Abbreviations 
ADA 
anti-drug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ASCT 
autologous stem cell transplant 
AST 
aspartate aminotransferase 
BMMC 
Bone marrow mononuclear cells 
CBC 
Complete Blood Chemistry 
CD 
Cluster of differentiation 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T lymphocyte-associated antigen 4  
DC 
Dendritic cell 
DLT 
dose-limiting toxicity 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good manufacturing practice 
HDT 
High dose therapy 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IGSF 
Immunoglobulin superfamily 
IHC 
Immunohistochemistry 
IMiD 
Immune modulatory drug 
IMP 
Investigational medicinal product 
IMWG 
International myeloma working group 
IND 
Investigational new drug 
IP 
Investigational product 
irAE 
Immune-related adverse event 
IRB 
Institutional Review Board 
IV 
intravenous 
LICR 
Ludwig Institute for Cancer Research 
mAb 
Monoclonal antibody 
MM 
Multiple Myeloma 
MSKCC 
Memorial Sloan Kettering Cancer Center 
MSSM 
Mt Sinai School of Medicine 
MTD 
maximum tolerated dose 


 
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NSCLC 
Non-small cell lung cancer 
NK 
Natural killer 
OS 
Overall survival 
PBL 
Peripheral blood leukocytes 
PBMC 
Peripheral blood mononuclear cell 
PD-1 
Programmed death-1  
PD-L 
Programmed death ligand 
POD 
Progression of disease 
PFS 
Progression free survival 
Q2W 
Every 2 weeks 
Q4W 
Every 4 weeks 
SAE 
Serious Adverse Event 
SCT 
Stem cell transplant 
TIL 
tumor-infiltrating lymphocyte 
ULN 
Upper limit of normal 
VDJ 
variable, diverse, and joining gene segments 
 


 
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Prot_001.pdf: 
LUD2014-010 (NCT02716805). A Phase 1 Study to Assess Safety and Tolerability of Tremelimumab and 
Durvalumab, Administered with High Dose Chemotherapy and Autologous Stem Cell Transplant (HDT/ASCT) 
Expanded Access Protocol for LUD2014-010 Cohort 1 Subjects Continuing Tremelimumab Treatment  
12September2017 
Page 1 of 7 
 
LUD2014-010 was initiated under IND 129021 for durvalumab. 
Six subjects have been enrolled into Cohort 1. One subject (050-001-YEY) has discontinued therapy due 
to disease progression as discussed below.  Five subjects remain on study. The dosing scheme for Cohort 
1 is provided below. 
 
A partial clinical hold on this study issued by FDA on September 1, 2017. LICR has implemented this 
partial clinical hold with the following immediate actions: 
• 
The Principal Investigators at the two participating sites have been notified and they have 
informed their IRBs. 
• 
No new patients will be entered into this study. 
• 
Durvalumab will be discontinued in Subject 017-001-TLD, and durvalumab will not be started in 
any other patient.  
• 
A decision to amend or discontinue this protocol will be made at a later date. 
• 
All subjects will be informed of the results of the pembrolizumab clinical studies in Multiple 
Myeloma, the FDA partial clinical hold and, if applicable, reconsented prior to additional study 
treatment. 
• 
Ongoing subjects receiving clinical benefit may remain on study treatment with tremelimumab. 
In discussions with the two Principal Investigators as well as the study chair for this study, it was their 
desire and recommendation that the 4 ongoing subjects who are now in the transplant phase of the 
study be permitted to continue the tremelimumab treatment portion of the study after being informed 
of the data from the two pembrolizumab studies in Multiple Myeloma and re-consented. These subjects 
will be treated in accordance with this expanded access protocol as outlined in the flowchart provided in 
Figure 1.  
This addendum references version 3 of the LUD2014-010 protocol, the most recent version submitted to 
IND 129021 and approved by the IRBs. This protocol will be followed, superseded by the updated 
information in this expanded access protocol including the schedule of events, as the LUD2014-010 
protocol has information that would be referenced, such as preparation and administration of 
tremelimumab,  AE reporting, toxicity management, and other important guidance. 


LUD2014-010 (NCT02716805). A Phase 1 Study to Assess Safety and Tolerability of Tremelimumab and 
Durvalumab, Administered with High Dose Chemotherapy and Autologous Stem Cell Transplant (HDT/ASCT) 
Expanded Access Protocol for LUD2014-010 Cohort 1 Subjects Continuing Tremelimumab Treatment  
12September2017 
Page 2 of 7 
 
In Table 1 on the following page, detailed information on the 4 subjects including their disease stage 
and prior therapies as well as the dates on the next protocol-scheduled treatment is provided.  
These four subjects have received tremelimumab pre-transplant and 3 of them have also received the 
tremelimumab together with the lymphocyte re-infusions on day 3 post-transplant. Based on 
discussions with the Principal Investigators at the two study sites as well as the study chair, it is believed 
that these subjects are obtaining clinical benefit from this treatment and therefore would like to 
continue treatment with tremelimumab up to and including the day 100 and day 100 + 4 weeks dosing 
and followed as per Figure 1. No durvalumab will be administered in cycles 3-8. These subjects may 
receive lenalidomide maintenance after Cycle 3 at the investigator’s discretion.


LUD2014-010 (NCT02716805). A Phase 1 Study to Assess Safety and Tolerability of Tremelimumab and Durvalumab, Administered with High Dose 
Chemotherapy and Autologous Stem Cell Transplant (HDT/ASCT) 
Expanded Access Protocol for LUD2014-010 Cohort 1 Subjects Continuing Tremelimumab Treatment  
12September2017 
Page 3 of 7 
 
 
Table 1: LUD2014-010 Subjects Continuing Tremelimumab Therapy 
 
Subject 
Age/Gender 
Site 
Date of 
Enrollment 
Tremelimumab 75 mg 
Administration 
Next steps 
 
 
017-002-OWU 
64/male 
MSKCC 
22-Aug-17 
1 dose 
Pre ASCT Day -31 
3 doses tremelimumab Day 3, day 100 
and day 128 
Next dose tremelimumab 9/28/2017 
 
Background/reason 
for continuing 
treatment 
Initially diagnosed with ISS I, IgA kappa MM in January 2012 after presenting with neck/back pain secondary to a C3 
plasmacytoma, s/p corpectomy, laminectomy with fixation from C3-C5, then RT, induction therapy with Velcade, 
thalidomide, and dexamethasone, and ASCT with melphalan, with overall VGPR. In June 2016, relapsed with new bone 
lesions and treated with ixazomib, Revlimid, and dexamethasone with PR. In December 2016, progression of disease 
(POD) and switched to carfilzomib, pomalidomide, and dexamethasone, achieving a VGPR. In May 2017, POD with rising 
serum markers, rib/back pain, multiple FDG-avid plasmacytomas, and high-risk cytogenetics. Received VD-PACE x2 (May 
and June 2017) with excellent response (near resolution of FDG-avid plasmacytomas) and enrolled on the study.  The 
patient has aggressive, multiply relapsed disease that is still chemosensitive, proving rationale for salvage ASCT with 
melphalan. However, due to the nature of his disease, he is at extremely high risk for early relapse after transplant. The 
addition of an immune modulatory agent, like tremelimumab, offers the potential to improve his response to salvage 
ASCT, beyond the limited benefits of available standard treatments. The patient is extremely motivated to participate 
and specifically requested this study during his initial transplant consultation at our center.  
 


LUD2014-010 (NCT02716805). A Phase 1 Study to Assess Safety and Tolerability of Tremelimumab and Durvalumab, Administered with High Dose 
Chemotherapy and Autologous Stem Cell Transplant (HDT/ASCT) 
Expanded Access Protocol for LUD2014-010 Cohort 1 Subjects Continuing Tremelimumab Treatment  
12September2017 
Page 4 of 7 
 
Subject 
Age/Gender 
Site 
Date of 
Enrollment 
Tremelimumab 75 mg 
Administration 
Next steps 
 
 
050-002-TRA 
55/female 
Mount Sinai 
4-May-17 
2 doses 
Pre ASCT Day -31 
PBL Day 3 
2 doses tremelimumab days 100 and 128. 
Next dose tremelimumab 10/20/2017 
 
Background/reason 
for continuing 
treatment 
Primary Dx: IgG Lambda MM diagnosed in 2011. BMBx with monotypic plasma cells,85% overall cellularity. Normal 
Karyotype 46, XX. Fish : gain of IGH and TP53 and trisomy 13 associated with intermediate prognosis in multiple 
myeloma  
1. 
First line tx- VRD x3 Melphalan with ASCT and maintenance Revlimid 15 mg. Rev reduced to 10 mg and then 5 
mg due to cytopenias. Then off treatment until first relapse.  
2. 
Second line treatment- Ludwig protocol LUD2014-010 
Reason for continuing treatment-:  Patient has responded very well to transplant with intermediate risk genetics. FLC 
have dropped from 201.75 to 9.28 and M-Spike has dropped from 0.94 to 0.00 on 60 days post-transplant without any 
SAE 
050-003-NUL 
59/male 
Mount Sinai 
7-Jun-17 
2 doses 
Pre ASCT Day -31 
PBL Day 3 
2 doses tremelimumab days 100 and 128. 
Next Dose tremelimumab 9/21/2017 
 
Background/reason 
for continuing 
treatment 
IgM Kappa MM, initially diagnosed ISS stage 1, DS stage II. Presented w/ T2 plasmacytoma. BMBx 5/16/16 with 5% PCs. 
FISH +TP53 deletion, monosomy 12 and gain 1q25. 
First Line- induction KRDx4/with Ludwig protocol LUD2014-010.  
Reason for continuing treatment:  Patient has high-risk genetics that have possible early relapse with relatively chemo 
resistance clone could have better clinical benefit with the addition of immunomodulatory agents and transplant.  
Patient has 0.00 m-spike 30 days post-transplant and did not have any SAE during infusion. 


LUD2014-010 (NCT02716805). A Phase 1 Study to Assess Safety and Tolerability of Tremelimumab and Durvalumab, Administered with High Dose 
Chemotherapy and Autologous Stem Cell Transplant (HDT/ASCT) 
Expanded Access Protocol for LUD2014-010 Cohort 1 Subjects Continuing Tremelimumab Treatment  
12September2017 
Page 5 of 7 
 
Subject 
Age/Gender 
Site 
Date of 
Enrollment 
Tremelimumab 75 mg 
Administration 
Next steps 
 
 
050-004-OLY 
62/female 
Mount Sinai 
27-Jun-17 
2 doses 
Pre ASCT Day -31 
PBL Day 3 
2 doses tremelimumab days 100 and 128. 
Next dose tremelimumab 11/13/2017 
 
Background/reason 
for continuing 
treatment 
Smoldering multiple myeloma IgA Lambda, diagnosed in July 9, 2013. Progressive increase in paraprotein without CRAB 
symptoms. Bone marrow on December 20, 2013. ISS stage I; Durie-Salmon stage IA.  The result is abnormal and indicates 
a plasma cell clone with a 1q duplication, monosomy 13, and FGFR3/IGH fusion, t(4;14). At diagnosis, t(4;14) and 1q 
duplication are associated with an intermediate prognosis in multiple myeloma   
1. First Line Therapy January 13, 2014: VRD x 5 cycles; CR 04/01/14. R25/D20 beginning 07/16/2014 for 6 cycles. 
R10/D4 maintenance. 
2. Biochemical Relapse March 2017. Ludwig Protocol LUD2014-010 
Reason for continuing treatment:  Patient has responded very well to transplant with greater than low risk genetics. M-
spike prior to transplant was 0.63 which has dropped to 0.0 after 30 days post-transplant. Patient has not had any SAE 
with infusion treatments. 
 


LUD2014-010 (NCT02716805). A Phase 1 Study to Assess Safety and Tolerability of Tremelimumab and 
Durvalumab, Administered with High Dose Chemotherapy and Autologous Stem Cell Transplant (HDT/ASCT) 
Expanded Access Protocol for LUD2014-010 Cohort 1 Subjects Continuing Tremelimumab Treatment  
12September2017 
Page 6 of 7 
 
Figure 1: Schedule of Procedures 
 
Study Flowchart for Cohort 1 
Screenin
g / 
Baseline 
Treatment  
Pre ASCT 
HDT 
/ASCT 
PBL 
Post ASCT and PBL  
Cycle 1 
Cycle 2 
Treatment  weeks (based on 
ASCT) 
-9 to -5 
  
1 
2 
5 
9 
14 
18 
Cycle Day 
  
1 
1 
Treatment days (based on 
ASCT) 
-62 to -34 
-
33±2 
-31±2 
-10 to -3 
-2 
0 
3  
12 
±4 
30 +10 
60±4 
100±10 
128±4 
Study Drugs and PBL Administration 
Tremelimumab (75 mg) 
  
  
X 
  
  
  
X2 
  
  
  
X 
X 
 Melphalan  
  
  
  
  
x 
  
  
  
  
  
  
  
Autologous Stem cell transplant 
(ASCT) 
  
  
  
  
  
x 
  
  
  
  
  
  
Peripheral blood lymphocyte 
(PBL) pheresis  
  
  
  
x 
  
  
  
  
  
  
  
  
PBL infusion 
  
  
  
  
  
  
X2 
  
  
  
  
  
Prevnar - 13 
  
X1 
  
  
  
  
  
  
x1 
x1 
  
  
Multiple Myeloma Tests 
PET/CT scan or MRI spine As 
clinically 
X 
  
  
  
  
  
  
  
  
  
x 
  
Myeloma serum tests5 
X 
  
  
x 
  
  
  
  
  
  
x 
x 
Myeloma urine tests5 
X 
  
  
x 
  
  
  
  
  
  
x 
x 
Study Procedures and Examinations 
Physical Exam (incl. weight and 
vitals) 
X 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
12-Lead ECG 
X 
  
  
  
  
  
  
  
  
  
  
  
ECHO- Heart Ultrasound  
X 
  
  
  
  
  
  
  
  
  
  
  
Lung Function tests 
X 
  
  
  
  
  
  
  
  
  
  
  
Routine Laboratory Samples 
Routine blood Test (chemistry 
and complete blood count)3 
-40 to -33 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Endocrine panel (Thyroid tests)3 
-40 to -33 
  
  
  
x 
  
  
  
  
  
x 
  
Urinalysis3 
-40 to -33 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum pregnancy test (urine 
test only on Day -31)3 
-40 to -33 
  
x 
  
  
x 
x 
  
  
  
x 
x 
Bone Marrow Samples 
Bone Marrow Sampling (tissue 
and aspirate) for routine and 
research laboratories 
x 
  
  
  
  
  
  
  
  
  
x 
  
Whole Blood for Research Labs 
Whole Blood Sampling for 
Research testing 
X 
X3 
 X3 
X4 
X3 
  
  
X3 
X3 
X3 
X3 
X3 
1. Prevnar dose and tremelimumab dose must be separated by a minimum of 48 hrs. 
2. Tremelimumab must be infused within 24 hours following PBL infusion 
3. Collect pre-dose (prior to drug administration) or other infusion. Note: It is strongly recommended that hematology, 
chemistry and pregnancy test (when applicable) results are reviewed before dosing. 
4. Samples will be removed from the pheresis product 
5. If serum and urine IF are positive, subsequent analysis is not necessary unless the subject achieves a response of VGPR or greater 
6. For subjects who did not experience progression while on study 
 
 
 


LUD2014-010 (NCT02716805). A Phase 1 Study to Assess Safety and Tolerability of Tremelimumab and 
Durvalumab, Administered with High Dose Chemotherapy and Autologous Stem Cell Transplant (HDT/ASCT) 
Expanded Access Protocol for LUD2014-010 Cohort 1 Subjects Continuing Tremelimumab Treatment  
12September2017 
Page 7 of 7 
 
Study Flowchart for Cohort 1 continued 
On Study Follow-up 
Post Study Follow-up 
Every 6 months for up 
to 2 years from start of 
treatment 
 
Cycle 3  
Cycle 3 or  
Last study drug 
+28  ±4 days 
Cycle 3 or  
Last study drug 
+56 ±4 days 
Cycle 3 or  
Last study drug 
+91 ±4 days  
End of Study 
 
Treatment  weeks (based on ASCT) 
22 
Cycle Day 
1 
Treatment days (based on ASCT) 
156 ±4 
  
  
  
Multiple Myeloma Tests 
PET/CT scan or MRI spine As clinically 
  
x 
  
  
Myeloma serum tests5  
x 
x 
  
Myeloma urine tests5 
x 
x 
  
Study Procedures and Examinations 
Physical Exam (incl. weight and vitals) 
x 
x 
x 
x 
  
12-Lead ECG 
  
x 
  
  
  
ECHO- Heart Ultrasound  
  
  
  
  
  
Lung Function tests 
  
  
  
  
  
Routine Laboratory Samples 
Routine blood Test (chemistry and complete blood 
count) 
x 
x 
x 
x 
  
Endocrine panel (Thyroid tests) 
x 
x 
  
x 
  
Urinalysis 
x 
x 
x 
x 
  
Serum pregnancy test (urine test only on Day -31)3 
  
x 
  
x 
  
Bone Marrow Samples 
Bone Marrow Sampling (tissue and aspirate) for routine 
and research laboratories 
  
x 
  
  
  
Whole Blood for Research Labs 
Whole Blood Sampling for Research testing 
x 
x 
  
Long-Term Follow-up 
 
 
 
Overall Survival 
 
 
x 
Progression Free Survival6 
 
 
x 
1. Prevnar dose and tremelimumab dose must be separated by a minimum of 48 hrs. 
2. Tremelimumab must be infused within 24 hours following PBL infusion 
3. Collect pre-dose (prior to drug administration) or other infusion. Note: It is strongly recommended that hematology, 
chemistry and pregnancy test (when applicable) results are reviewed before dosing. 
4. Samples will be removed from the pheresis product 
5. If serum and urine IF are positive, subsequent analysis is not necessary unless the subject achieves a response of VGPR or greater 
6. For subjects who did not experience progression while on study