Clinical trial NCT03082677
Conditions: Myeloid Hematologic Malignancy Lymphoid Hematologic Malignancy
Keywords: Ixazomib Graft-versus-Host Disease Allogeneic Hematopoietic Stem Cell Transplantation 16-076
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2017-03-10; Completion date: 2021-09-02
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single arm open label phase 2 study evaluating the potential effect of ixazomib on the prevention of recurrent or late acute graft-versus-host disease (GVHD) and chronic GVHD at 1-year following reduced intensity (RI) or non-myeloablative (NMA) allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of hematologic malignancies.

Detailed description:

Arms: arm 1: Ixazomib beginning between day +100 to +150 at a dose of 4 mg orally once per week (3 weeks on/ 1 week off). The patients will continue on this same dose until taper off from immunosuppressants or 1 year post-HSCT is reached (whichever occurs first) or until the patient develops GVHD or malignant disease relapse/progression occurs.
Interventions: intervention 1: Ixazomib
Intervention descriptions: intervention 1: Ixazomib beginning between day +100 to +150 at a dose of 4 mg orally once per week (3 weeks on/ 1 week off).

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 16-076 A(4) 
Page 1 of 36 
 
 
Approval date: 09-Jan-2018 
Open Label Phase II Study of Ixazomib for the Prevention of R
Acute and Chronic Graft-versus-Host Disease at 1-year afte
Hematopoietic Stem Cell Transplantation in Patients
Hematologic Malignancies 
PROTOCOL FACE PAGE FOR 
MSK THE RAPEUTIC /D IAGNOSTIC PROTOCO
Principal Investigator/Department: 
Doris M. Ponce, MD 
ecurrent or Late 
r Allogeneic 
with 
L 
Medicine 
Co-Principal 
Craig Sauter, MD 
Investigator(s)/Department: 
Sergio Giralt, MD 
Medicine 
Medicine 
Investigator(s)/Department: 
Sean Devlin, Ph.D 
Patrick Hilden, M.S 
Juliet N. Barker, M.B.B.S (Hons) 
Hugo Castro-Malaspina, MD 
Christina Cho, MD 
David Chung, MD, Ph.D 
Parastoo Dahi, MD 
Bloglarka Gyurkocza, M.D 
Alan Hanash, MD, Ph.D 
Katharine C. Hsu, M.D., Ph.D 
Ann A. Jakubowski, MD, Ph.D 
Scott James, MD, Ph.D 
Oscar Lahoud, MD 
Heather Landau, MD 
Esperanza B. Papadopoulos, MD 
Jonathan Peled, MD 
Miguel-Angel Perales, MD 
Ioannis Politikos, MD 
Michael Scordo, MD Brian 
Shaffer, MD 
Gunjan Shah, MD 
Melody Smith, MD 
Roni Tamari, MD 
Marcel R. M. van den Brink, MD, Ph.D 
James W. Young, MD 
Elaina Preston, PA 
Abigail Cohen, NP 
Carter Hibbs, NP 
Shani Irby, NP 
Stefanie Kelly, NP 
Sheila Kenny, NP 
Nicole LeStrange, NP 
Chelsea Mintz, NP 
Emily Patterson, NP 
Megan Heavey Scott, NP 
Christianne Supan, NP 
Allison Tucker, NP 
Tara Wolff, NP 
Natasia Rodriguez, RN 
Biostatistics 
Biostatistics 
Medicine 
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Nursing 
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Page 2 of 36 
Memorial Sloan Kettering Cancer Center 
IRB Number: 16-076 A(4) 
Approval date: 09-Jan-2018 
 
 
 
 
 
Consenting  Professional(s)/Department: 
Juliet N. Barker, M.S.S.B (Hons) 
Medicine 
Hugo Castro-Malaspina, MD 
Medicine 
Christina Cho, MD 
Medicine 
David Chung, MD, PhD 
Medicine 
Parastoo Dahi, MD 
Medicine 
Sergio Giralt, MD 
Medicine 
Bloglarka Gyurkocza, MD 
Medicine 
Alan Hanash, MD, PhD 
Medicine 
Katharine C. Hsu, MD, PhD 
Medicine 
Ann A. Jakubowski, MD, PhD 
Medicine 
Scott James, MD, Ph.D 
Medicine 
Oscar Lahoud, MD 
Medicine 
Heather Landau, MD 
Medicine 
Matthew Matasar, MD 
Medicine 
Esperanza B. Papadopoulos, MD 
Medicine 
Jonathan Peled, MD 
Medicine 
Miguel-Angel Perales, MD 
Medicine 
Ioannis Politikos, MD 
Medicine 
Doris M. Ponce, MD 
Medicine 
Craig Sauter, MD 
Medicine 
Michael Scordo, MD 
Medicine 
Brian Shaffer, MD 
Medicine 
Gunjan Shah, MD 
Medicine 
Melody Smith, MD 
Medicine 
Roni Tamari, MD 
Medicine 
Marcel R. M. van den Brink, MD, PhD 
Medicine 
James W. Young, MD 
Medicine 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
 
 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-076 A(4) 
Approval date: 09-Jan-2018 
Page 3 of 36 
 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ...................................................................... 4 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ............................................................................... 4 
3.0 
BACKGROUND AND RATIONALE ..................................................................................... 5 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................. 12 
4.1 Design ................................................................................................................................ 12 
4.2 Intervention .............................................................................................................................. 12 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ........................................................................... 12 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .............................................................................. 13 
6.1 Subject Inclusion Criteria .................................................................................................... 13 
6.2 Subject Exclusion Criteria ................................................................................................... 14 
7.0 
RECRUITMENT PLAN ................................................................................................................... 15 
8.0 
PRETREATMENT EVALUATION ...................................................................................... 15 
9.0 
TREATMENT/INTERVENTION PLAN ............................................................................... 15 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION .................................................... 20 
11.0 
TOXICITIES/SIDE EFFECTS .................................................................................................... 22 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ........................ 24 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ....................................................................... 26 
14.0 
BIOSTATISTICS ............................................................................................................... 26 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES28 
15.1 Research Participant Registration ......................................................................................... 28 
15.2 
Randomization ................................................................................................................... 28 
16.0 
DAT A M ANAGEMENT ISSUES ........................................................................................ 28 
16.1 
Quality Assurance ........................................................................................................ 28 
16.2 
Data and Safety Monitoring .............................................................................................. 29 
17.0 
PROTECTION OF HUMAN SUBJECTS ............................................................................ 29 
17.1 
Privacy .......................................................................................................................... 29 
17.2 
Serious Adverse Event (SAE) Reporting ......................................................................... 29 
17.2.1.........................................................................................................................................31 
18.0 
INFORMED CONSENT PROCEDURES .................................................................................. 34 
19.0 
REFERENCES ...................................................................................................................... 35 
20.0 
APPENDICES ................................................................................................................... 36 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-076 A(4) 
Approval date: 09-Jan-2018 
Page 4 of 36 
 
 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is a single arm open label phase 2 study evaluating the potential effect of ixazomib on 
the prevention of recurrent or late acute graft-versus-host disease (GVHD) and chronic 
GVHD at 1-year following reduced intensity (RI) or non-myeloablative (NMA)  allogeneic 
hematopoietic stem cell transplantation (HSCT) for the treatment of hematologic 
malignancies. Patients will be eligible for enrollment if they are without active acute or  
chronic GVHD  between days +100 and +150 following HSCT. After enrollment patients will 
initiate treatment with ixazomib and continue until  all immunosuppressants are tapered off or 
1 year post-HSCT is reached (whichever occurs first) or grade II-IV acute and/or chronic 
GVHD develops or malignant disease relapse/ progression occurs. The primary aim is to 
assess the incidence of development of grade II-IV recurrent or late acute GVHD (aGVHD) 
and chronic GVHD (cGVHD) at 1-year following ixazomib administration post-HSCT. 
Calcineurin inhibitor based drug and methotrexate (MTX) will be used for initial GVHD 
prophylaxis. Ixazomib will be used as secondary GVHD prophylaxis as above. 
 
Patients will be monitored post-transplant for incidence and severity of recurrent or late acute 
and cGVHD at 1-year post-HSCT, transplant-related mortality (TRM), characteristics of 
immune recovery, as well as overall and event-free survival. 
 
Protocol Schema 
 
 
 
 
 
 
 
+100 to +1 year 
 
Ixazomib 4 mg PO once a week. Cycles are every 28 days (3 weeks on/ 1 week off) until 
discontinuation of immunosuppressants or 1 year post-HSCT (whichever occurs first), or 
grade II-IV acute or chronic GVHD develops or malignant disease relapse/ progress ion 
occurs. 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
The primary aim is to assess the efficacy of ixazomib for the prevention of recurrent or late 
grade II-IVa GVHD or chronic GVHD at 1 year post-transplant. 
 
Secondary objectives include: 
• 
the incidence of overall and moderate/severe cGVHD. 
• 
the incidence of transplant-related mortality (TRM). 
• 
the incidence of disease progression. 
• 
the incidence of grade II-IV and III-IV acute GVHD 
• 
the probabilities of overall and progression-free survival after HSCT. 
Ixazomib 
4 weeks cycles 
(3 weeks on/ 1 week off) 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-076 A(4) 
Approval date: 09-Jan-2018 
Page 5 of 36 
 
 
 
 
 
• 
proportion  of  subjects  with  discontinuation  of  immunosuppressive  medication 
after 
HSCT. 
• 
Characteristics of immune reconstitution 
 
Exploratory objectives include: 
• 
Describe the percentage of patients who get vaccines on time and percentage of 
patients who do not respond to vaccines. 
• 
Describe treatment failure for patients who enroll on post-transplant day  +100 to 
+125 and for patients who enroll on post-transplant day +125 to  +150. 
 
Safety endpoints: 
• 
Incidence and severity of adverse events (AEs) and serious AEs (SAEs). 
 
3.0 
BACKGROUND AND RATIONALE 
 
GVHD is a frequent and at times unpredictable severe complication of HSCT1-3, and is a 
leading cause of TRM following HSCT1,4. GVHD can be characterized as acute or chronic, 
based on the clinical manifestation5. Acute GVHD damages the skin, gut,  and/or  liver. 
Nausea, vomiting, abdominal pain, diarrhea, bloody stool and/or jaundice are commonly 
present. While calcineurin-inhibitor based GVHD prophylaxis has decreased the incidence 
and mortality associated with aGVHD, it provides inadequate protection since this disease 
commonly affects > 50% of HSCT recipients6. Risk factors associated with aGVHD include 
recipients of sex-mismatched HSCT and/or HLA-mismatched donor, peripheral blood stem 
cell graft and myeloablative conditioning7,8. The incorporation of an additional prophylactic 
agent could potentially decrease the incidence of GVHD development and ameliorate 
transplant 
complications including 
TRM. 
However, 
in 
RI 
and NMA 
conditioning 
transplantation, critically dependent of graft-versus-tumor effect for cure, in vivo T-cell 
antibody based GVHD prophylaxis (i.e. anti-thymocyte globulin) can also impair survival9. 
Thus, novel T-cell replete GVHD regimens would be of considerable utility. 
 
For the patients who develop grade II-IV aGVHD, the standard first-line treatment is oral or 
IV corticosteroids10. It is difficult to predict at the onset of aGVHD who will respond fully or 
partially, or who will be refractory. Approximately 50% of patients will not achieve a sustained 
complete response of aGVHD to first-line therapy with corticosteroids6. For those patients 
who fail to respond to 
corticosteroids 
additional 
immunosuppressive agents 
are 
necessary
11,12. Unfortunately, survival is poor in steroid-resistant aGVHD at approximately 
15% at 2 years13. 
Acute GVHD may develop after day 100. Recurrent aGVHD is defined as recurrence of 
clinical findings of aGVHD after day 100 whereas late aGVHD is non-chronic GVHD features 
occurring after 100 days post transplant5. The former, occurs more often after transplants 
that utilize RI and NMA
14 . Chronic GVHD is diagnosed based on established criteria outlined 
at the NIH consensus conference
5. In general, cGVHD is characterized to varying degrees 
by sclerosis of lacrimal and salivary ducts, scleroderma-like changes of the skin, chronic 
inflammation and scarring of the gastrointestinal tract with consequent malabsorption and 
diarrhea, inflammation of the liver, suppression of the immune system and occasionally other 
auto-immune phenomena (such as, auto-immune hemolysis) or involvement of other organs 
(such  as,  pulmonary  involvement).  Chronic  GVHD  is  diagnosed  and  graded  as  mild, 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-076 A(4) 
Approval date: 09-Jan-2018 
Page 6 of 36 
 
 
 
 
moderate or severe5. While patients with moderate or severe manifestation generally need 
systemic therapy, usually including corticosteroids, the treatment of  cGVHD  can change 
based on organ system involvement. While reducing the intensity of the preparative regimen 
has decreased the incidence of early presentations of aGVHD, the incidence of cGVHD has 
not been affected by this change of practice14,15. 
3.1 Graft-versus-host 
Disease 
after Reduced 
Intensity and 
Non-Myeloablative 
Transplantation 
The Center for International Blood and Marrow Transplant Research evaluated the outcomes 
of 1676 patients who underwent allogeneic HSCT after RI conditioning9. They found that 
patients who received a T-cell replete regimen had a 3-year incidence of cGVHD of 52% 
(95%CI: 49-56) whereas patients who had alemtuzumab-containing and ATG-containing 
regimens had a lower incidence of 24% (95%CI: 18-30) and 40% (95%CI: 36-44), 
respectively, p = <0.001. However, the risk of 3-year relapse was lower in the T-cell replete 
regimen when compared to alemtuzumab-containing and ATG-containing regimens (38% vs 
51% vs 49%). Similarly, disease-free survival was higher in the T-cell replete regimen than 
those who received in vivo T-cell depleted regimens. 
Mielcarek et al analyzed GVHD according to conditioning regimen intensity in 96 allograft 
recipients
14. The incidence of grade II-IV aGVHD at day 100 was higher in the myeloablative 
conditioning recipients of 77% when compared to that of 62% in NMA conditioning recipients 
(p = 0.02) whereas grade III-IV severe aGVHD was  similar (p = 0.89) This  comparison 
revealed that the median time to initiation of corticosteroids for treatment of GVHD was 
delayed by more than 2 months (median time 3.0 months) in the NMA group when compared 
to the myeloablative recipients (median time 0.95 months). These findings suggest that the 
median onset of GVHD is delayed in NMA conditioning recipients. The probability of cGVHD 
was similar among for recipients of NMA and myeloablative conditioning (77% vs 74%, p = 
0.37). 
 
Ceberio et al evaluated 71 patients with hematologic malignancies who received  either 
reduced RI (n = 12) or NMA (n = 59) conditioning followed by allogeneic HSCT15. GVHD 
prophylaxis consisted of sirolimus, tacrolimus and low-dose methotrexate. The analysis 
showed a cumulative incidence of grade II-IV and III-IV aGVHD at 1 year of 28% (95%CI: 18- 
39) and 7% (95% CI: 3-15), respectively. The median onset of aGVHD was day 123 (range 
17-268) and the majority of the patients who developed aGVHD occurred in the context of 
immunosuppression tapering. The cumulative incidence of chronic GVHD in 70 evaluable 
patients at 1 year was 15% (95% CI: 8-24) and 2 years was 32% (95%CI: 22-44). 
 
The results of a prospective phase II trial assessing peri-transplant rituximab with a NMA 
conditioning regimen for patients with CD20 B cell NHL was recently published by Sauter et 
al from the adult transplantation group at Memorial Sloan Kettering Cancer Center16. The 
data from this study (n = 51) reveals a promising 2-year event-free survival (EFS) in this 
group of patients; the EFS was 84% and 40% for chemosensitive as compared to 
chemotherapy refractory patients before allo-HSCT. The cumulative incidence of grade II-IV 
aGVHD at 3 and 6 months after HSCT was 18% (95%CI: 7-29) and 25% (95%CI: 13-38), 
respectively, whereas the cumulative incidence of severe grade III-IV aGVHD at 3 and 6 
months  was  8%  (95%CI:  0-16)  and  11%  (95%CI:  3-24),  respectively.  The  cumulative 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-076 A(4) 
Approval date: 09-Jan-2018 
Page 7 of 36 
 
 
 
 
incidence of moderate to severe cGVHD at 1 year was 14% (95%CI: 3-24) and at 2 years 
was 29% (95%CI: 15-44). Notable, GVHD was noted to be a more frequent cause of death 
than disease relapse or progression. The number of patients who suffered a transplant- 
related event (most of which were due to GVHD) was 20 (19%), while the number of patients 
who relapsed or progressed was 14 (13%). In particular, in those patients with FL, there was 
one disease-related event and 9 transplant-related events. In a follow-up analysis as of 
September 1, 2014, 46 patients were alive without progression of disease at day 100. Of 
those, the development of any GVHD syndrome was assessed. This analysis demonstrated 
a cumulative incidence of 63% (95%CI: 47-76) at 1-year of any GVHD syndrome. Thirty-five 
percent (n = 16) had no active GVHD whereas 30 patients had active GVHD syndrome. The 
predominant manifestation was late onset aGVHD (n = 9, 19.5%) and overlap syndrome (n = 
9, 19.5%), followed by classical chronic GVHD (3 interrupted, 4 de novo) and recurrent 
aGVHD (n = 5, 11%) (unpublished data). 
3.2 
Proteosome inhibitors to reduce GVHD 
 
The proteasome inhibitor, bortezomib, has immunomodulatory properties with the ability to 
selectively deplete proliferating alloreactive T lymphocytes, reduce T-helper type 1 cytokines, 
and block antigen presenting cell activation
17,18. Bortezomib may also spare regulatory T- 
cells (Treg) that may be relevant in GVHD control. In a phase I/II trial at Dana Farber Cancer 
Institute19, Koreth el al evaluated Bortezomib-based regimen for  the  prophylaxis  against 
GVHD for patients who received HLA-mismatched unrelated donor transplant after RI 
conditioning regimen. GVHD prophylaxis consisted of tacrolimus, methotrexate and 
Bortezomib. A total of 45 patients were enrolled on this trial in which bortezomib was given 
on days  +1, +4, and +7. Toxicities  included cytopenias  and infections, not deemed to be 
related to the study drug. The cumulative incidence of grade II-IV aGVHD at 180 days was 
22% whereas the cumulative incidence of cGVHD at 12 months was 29%. Additionally, the 
cumulative incidence of non-relapse mortality at 2 years was 11%. Given these results, the 
authors surmised that bortezomib is a promising novel immune modulatory agent that may 
decrease GVHD following allo-HSCT. 
The effect of Bortezomib on cGVHD was also assessed in a murine model
20. This study 
demonstrated that Bortezomib ameliorated cGVHD cutaneous lesions, which were also 
associated with a reduction in total numbers of germinal center B cells and lower B-cell 
activating factor gene expression levels in cutaneous lesions. Pai et al conducted a dose 
escalation clinical trial in patients with steroid-intolerant, dependent or resistant20.  Ten 
patients received Bortezomib, of those, 6 received >60% of the scheduled doses and 5 of 6 
patients responded to therapy, achieving a marked clinical improvement, which was also 
associated with reductions of peripheral B cells and minimal toxicity. In the majority of the 
responders, the dose and/or number of immunosuppressive drug therapies were reduced 
during treatment with Bortezomib. 
3.2.1    Ixazomib 
 
Ixazomib has been evaluated as an oral single agent in phase 1 studies that have included 
patients with advanced solid tumors, lymphoma, relapse/refractory multiple myeloma (MM), 
and  relapsed  or  refractory  light-chain  (AL)  amyloidosis.  In   addition,  ongoing  clinical 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-076 A(4) 
Approval date: 09-Jan-2018 
Page 8 of 36 
 
 
 
 
pharmacology studies include evaluation of drug-drug interactions with ketoconazole and 
rifampin, effect of food, and oral bioavailability. Studies evaluating the safety and 
pharmacokinetic (PK) of ixazomib are ongoing. Preliminary clinical data is available for a total 
of 653 patients across 13 studies. The emerging safety profile indicates that ixazomib is 
generally well tolerated. 
Targeting T cells alone has yielded limited success in the prevention of GVHD following 
allogeneic HSCT. Dendritic cells play a role in alloreactivity  and therefore,  represent  a 
suitable target. Proteasome inhibitors have the ability to inhibit the function and maturation of 
dendritic cells, which have prompted investigators to evaluate their potential role in the 
prevention of GVHD. Ixazomib is the first oral proteasome inhibitor that dissociates rapidly 
from 20S proteasome, and therefore, is truly reversible. Ixazomib has demonstrated immune 
modulatory effects, inhibition of maturation and function of dendritic cells, inhibition of pro- 
inflammatory cytokines production in dendritic cells, and inhibition  of  T-cell  proliferation. 
These effects suggest a potential role of this drug in the prevention of acute and chronic 
GVHD. While proteasome inhibitor bortezomib has demonstrated efficacy in the prophylaxis 
and treatment of GVHD, its administration by intravenous or subcutaneous route require 
frequent hospital visits and monitoring which can limit its use in the  outpatient  setting. 
Ixazomib may overcome this limitation since is orally bioavailable and is associated with 
favorable safety and toxicity profile. 
3.2.1.1 Pharmacokinetics and drug metabolism 
 
Clinical intravenous and oral PK data show that ixazomib citrate (measured as the 
biologically active boronic acid form of  ixazomib  [MLN2238])  has  multi-exponential 
disposition with a rapid initial phase that is largely over by 4 hours. Oral ixazomib citrate is 
rapidly absorbed with a median single-dose first time of occurrence of maximum (peak) 
concentration (Tmax) of approximately 0.5 to 2.0 hours and a terminal disposition half-life 
(t1/2) after multiple dosing of approximately 5 to 7 days
21. Results of  a  population  PK 
analysis (n = 137) show that there is no relationship between body surface area (BSA) or 
body weight and clearance (CL). Also, based on stochastic  simulations for fixed dose, 
exposures are independent of the individual patient’s BSA
22. Therefore, fixed dosing was 
recommended in clinical trials. An absolute bioavailability of 67% was determined for 
ixazomib using the population PK analysis. 
 
Metabolism appears to be the major route of elimination for ixazomib, and urinary excretion 
of the parent drug is negligible (< 5% of dose). In vitro studies indicate that ixazomib is 
metabolized by multiple cytochrome P450s (CYPs) and non-CYP enzymes/proteins. The 
rank order of relative biotransformation activity of the 5 major human CYP isozymes was 3A4 
(34.2%) > 1A2 (30.7%) > 2D6 (14.7%) > 2C9 (12.1%) > 2C19 (< 1%). Ixazomib is not an 
inhibitor of CYPs 1A2, 2C9, 2C19, 2D6, or 3A4 nor a time-dependent inhibitor of CYP3A4/5. 
The  potential  for  ixazomib  treatment  to  produce  drug-drug  interactions  (DDIs)  via  CYP 


Memorial Sloan Kettering Cancer Center 
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Page 9 of 36 
 
 
 
 
inhibition is inferred to be low. However, there may be a potential for DDIs with a concomitant 
strong CYP3A4 or CYP1A2 inhibitor or inducer because of the potential for first-pass 
metabolism when ixazomib is administered via the PO route and because of the moderate 
contribution of CYP3A4- and CYP1A2-mediated metabolism of ixazomib in human liver 
microsomes. Ixazomib may be a weak substrate of P-glycoprotein (Pgp), breast cancer 
resistance protein (BCRP), and multidrug resistance associated protein (MRP2) efflux pump 
transporters. Ixazomib is not an inhibitor of Pgp, BCRP, and MRP2. The potential for DDIs 
with substrates or inhibitors  of Pgp, BCRP, and MRP2 is, therefore, inferred to be low. 
Clinical Study C16009 (Arm 1) with ketoconazole, a strong CYP3A4 inhibitor, showed a 2- 
fold increase in area under the plasma concentration versus time curve (AUC) in  the 
presence of ketoconazole23. This resulted in the exclusion of concurrent use of  strong 
CYP3A4 inhibitors proteasome inhibitor/ ixazomib. 
 
3.2.1.2. Ixazomib safety profile 
 
The emerging safety profile indicates that ixazomib is generally well tolerated. The adverse 
events (AEs) are consistent with the class-based effects of proteasome inhibition and are 
similar to what has been previously reported with VELCADE though the severity of some, for 
example peripheral neuropathy, is less. While some of these potential toxicities may be 
severe, they can be managed by clinical monitoring and standard medical intervention, or, as 
needed, dose modification or discontinuation. 
Fatigue was the most common AE reported among 384 patients treated in the oral studies 
(47%). Other common AEs reported in the pooled intravenous and oral safety populations 
include nausea, thrombocytopenia, diarrhea, and vomiting. Rash is also a commonly 
reported treatment-emergent event; however, there is some variety in its characterization 
and causality resulting in different preferred terms to describe it. A high-level term outline of 
rash events includes rashes, eruptions and exanthems NEC; pruritus NEC; erythema; 
papulosquamous conditions; and exfoliative conditions. The dose escalation phases of most 
trials reported in the IB have now completed enrollment, and gastrointestinal (GI) symptoms 
were the common dose-limiting toxicities (DLTs) when the use of prophylactic anti-emetics 
was not permitted per protocol. In the expansion cohorts or phase 2 cohorts (as per each 
study), the incidence and severity of GI symptoms was mitigated by the use of the lower 
maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) (as per each study) 
and standard clinical usage of anti-emetics and/or antidiarrheal medications as deemed 
appropriate. Prophylactic use of anti-emetics has not been required as with other agents but 
has been used according to standard practice and are effective. 
The most frequent (at least 20%) treatment-emergent adverse events (TEAEs) reported with 
the PO formulation pooled from single-agent studies (n = 201) irrespective of causality to 
ixazomib, include nausea (53%), fatigue (51%), diarrhea (44%), thrombocytopenia (34%), 
vomiting (38%), decreased appetite (32%), fever (21%), and anemia (21%) (Table 3.2.1.2). 


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IRB Number: 16-076 A(4) 
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Page 10 of 36 
 
 
 
 
The most frequent (at least 20%) TEAEs reported with the PO formulation pooled from 
combination trials (irrespective of the combination) (n = 173), irrespective of causality to 
ixazomib, include diarrhea (47%), fatigue (44%), nausea (38%), peripheral edema (35%), 
constipation  (33%),  insomnia  (29%),  thrombocytopenia  (28%),  anemia  (26%),  vomiting 
(26%), neutropenia (25%), back pain (24%), pyrexia (23%), peripheral edema (21%, each), 
fever (20%), cough (20%), hypokalemia (20%), neutropenia (20%), and upper respiratory 
tract infection (20%). Overall rash of all grades is reported in approximately 50% of patients 
and is more common when ixazomib is given in combination with lenalidomide where rash is 
an overlapping toxicity. 
 
 
 
Table 3.2.1.2   Most Common (At Least 10% of Total) Treatment-Emergent Adverse 
Events in Oral Single-Agent Studies 
 
 
 
 
Primary System Organ Class 
Preferred Term 
Subjects with at Least One 
Adverse Event 
Oral Single Agent 
Total 
n = 201 
n (%) 
197 (98) 
Gastrointestinal disorders 
160 (80) 
Nausea 
106 (53) 
Diarrhea 
88 (44) 
Vomiting 
77 (38) 
Constipation 
46 (23) 
Abdominal pain 
33 (16) 
General disorders and 
administration site conditions 
151 (75) 
Fatigue 
103 (51) 
Pyrexia 
51 (25) 
Oedema peripheral 
27 (13) 
Asthenia 
31 (15) 
Nervous system disorders 
92 (46) 
Headache 
29 (14) 
Dizziness 
26 (13) 
Neuropathy peripheral 
21 (10) 
Metabolism and nutrition disorders 
107 (53) 
Decreased appetite 
64 (32) 
Dehydration 
37 (18) 
Blood and lymphatic system 
disorders 
98 (49) 
Thrombocytopenia 
68 (34) 


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Page 11 of 36 
 
 
 
 
 
Table 3.2.1.2   Most Common (At Least 10% of Total) Treatment-Emergent Adverse 
Events in Oral Single-Agent Studies 
 
 
 
 
Primary System Organ Class 
Preferred Term 
Oral Single Agent 
Total 
n = 201 
n (%) 
 
 
Anaemia 
42 (21) 
Neutropenia 
29 (14) 
Lymphopenia 
20 (10) 
Skin and subcutaneous tissue 
disorders 
90 (45) 
Rash maculara 
23 (11) 
Musculoskeletal and connective 
tissue disorders 
93 (46) 
Back pain 
24 (12) 
Arthralgia 
28 (14) 
Respiratory, thoracic and 
mediastinal disorders 
78 (39) 
Cough 
28 (14) 
Dyspnea 
30 (15) 
Infections and infestations 
89 (44) 
Upper respiratory tract infection 
31 (15) 
 
 
Abbreviations:  MedDRA = Medical Dictionary for Regulatory Activities, version 15.0. 
Subject Incidence:  A subject counts once for each preferred term.   Percentages use the number 
of treated subjects as the denominator. 
a  Note that rash maculopapular and rash macular represent the 2 most common terms used to 
describe rash. 
 
The clinical experience with ixazomib also shows early signs of antitumor activity as 
evidenced by at least a 50% reduction in disease burden in some patients and prolonged 
disease stabilization in others across all ongoing trials. The antitumor activity has been seen 
with single-agent ixazomib, when combined with established therapies, and across the 
malignancies studied including non-Hodgkin’s disease and Hodgkin’s disease24. 
3.3  Summary 
 
GVHD is frequent after HSCT and is a major cause of TRM. Previous analyses of patients 
with hematologic malignancies treated with RI or NMA conditioning followed by HSCT reveal 
that GVHD usually develops after day 100 and particularly during immunosuppression 
tapering. Thus, using another agent for the prevention of GVHD after day 100 could 
potentially decrease the incidence and ameliorate GVHD-related mortality. Additionally, past 
experience with proteasome inhibitors to reduce GVHD  supports  further  investigation  of 
these agents.   As  such, the use of ixazomib, which is  an oral proteasome inhibitor with 


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Page 12 of 36 
 
 
 
 
minimal  neurotoxicity,  is  an  optimal  candidate  to  add  in  this  setting  in  an  effort  to 
prophylactically decrease GVHD development. 
The primary aim of this study is to assess the efficacy of ixazomib for the prevention of 
recurrent or late acute grade II-IV GVHD or chronic GVHD at 1-year post-transplant. We will 
administer ixazomib starting within days 100 to 150 after HSCT. This window has been 
chosen so as to allow count recovery post-transplant prior to starting an agent that may 
cause cytopenias. This study drug will be added to our standard approach for the prevention 
of GVHD. Patients will have received a RI or NMA conditioning for the treatment of their 
myeloid or lymphoid hematologic malignancy, followed by an 8/8 or 7/8 HLA-matched 
volunteer donor HSCT, and the combination of calcineurin inhibitor based drug (either 
tacrolimus or cyclosporin) and methotrexate for GVHD prophylaxis. Given that ixazomib is an 
oral proteasome inhibitor that is given once weekly, this additional agent to the post- 
transplant treatment regimen will be convenient for patients. After enrollment, patients will 
initiate treatment with ixazomib  and continue until all immunosuppressants are tapered off or 
1 year post-HSCT (whichever occurs first), or grade II-IV acute or chronic GVHD develops or 
malignant disease relapse/ progression occurs. 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is a single arm phase 2 study to evaluate a post-transplant proteasome inhibitor, 
ixazomib, as prophylaxis against recurrent or late acute and chronic GVHD.  Ixazomib will be 
initiated within days 100 to 150 post-transplant in patient’s > 18 years-old with either myeloid 
or lymphoid hematologic malignancy treated with a RI or NMA HSCT and will have received 
calcineurin inhibitor based drug (tacrolimus or cyclosporin) and methotrexate as part of their 
initial GVHD prophylaxis. 
 
4.3 
Intervention 
 
The primary aim is to assess the efficacy of ixazomib for the prevention of recurrent or late 
grade II-IV aGVHD or chronic GVHD at 1-year post-transplant. The accrual period will be 
approximately 3 years with an additional 12 months of follow-up after the accrual period has 
been completed. Stopping rules are in place for secondary graft failure without autologous 
recovery and excessive treatment related toxicity. The target sample size for this study is 46 
patients with an approximate accrual of 16 patients per year. 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
If appropriate describe packaging, labeling and storage requirements of the agents and/or 
device(s). Indicate any special instructions for maintaining, tracking and monitoring that is 
required by sponsor, FDA and/or MSKCC. 
5.1       MLN 9708 (Ixazomib) 
Supplied as: strengths of 4.0-, 3.0-, and 2.3-mg and 2.0-, 0.5-, and 0.2 mg capsules as the 
active boronic acid. The study drug will be supplied by Takeda Pharmaceuticals/ Millennium 


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as capsules of 0.2-, 0.5-, and 2.0 mg, or as capsules of 2.3-, 3.0- and 4.0 mg ixazomib. This 
is dependent on available ixazomib formulation. 
 
Reconstitution directions: N/A. 
 
Storage and stability: on receipt at the investigative site, study drug should remain in the 
blister and carton provided until use or dispensation. The container should be stored 
refrigerated (36°F to 46°F, 2°C to 8°C). All excursions should be brought to the sponsor’s 
attention for assessment and authorization for continued use. Ensure that the drug is used 
before the retest expiry date provided by Takeda Pharmaceuticals/ Millennium. Expiry 
extensions will be communicated accordingly with updated documentation to support the 
extended shelf life. 
 
Study drug dispensed to the patient for take-home dosing should remain in the listed 
packaging and carton and refrigerated as noted above until the point of use. Comprehensive 
instructions should be provided to the patient in order to ensure compliance with dosing 
procedures. Patients should be instructed to store the medication refrigerated (36°F to 46°F, 
2°C to 8°C) for the duration of each cycle. Patients should be instructed to return their empty 
carton to the investigative site, rather than discarding them. 
 
Reconciliation will occur accordingly when the patient returns for their next cycle of take- 
home medication. Any extreme in temperature should be reported and dealt with on a case- 
by-case basis. 
 
Preparation: Patients should be instructed to swallow ixazomib capsules whole, with water, 
and not to break, chew, or open the capsules. Study drug should be taken on an empty 
stomach (no food or drink) at least 1 hour before or 2 hours after a meal. Each capsule 
should be swallowed separately with a sip of water. 
 
Clinical considerations: Missed doses can be taken as soon as the patient remembers if the 
next scheduled dose is 72 hours or more away. A double dose should not be taken to make 
up for a missed dose. If the patient vomits after taking a dose, the patient should not repeat 
the dose but should resume dosing at the time of the next scheduled dose. 
 
Hydration: A total of approximately 8 ounces (240 mL) of water should be taken with the 
capsules. 
 
Toxicities: see section 11.0 
 
Incompatibilities: with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin,  ciprofloxacin), 
strong inhibitors 
of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, 
ketoconazole, nefazodone, posaconazole), or strong CYP3A inducers (rifampin, rifapentine, 
rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John’s 
wort. 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
Describe the characteristics of the patient/subject population. 
 
6.2 
Subject Inclusion Criteria 


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Eligible patients will be consented by the Adult BMT service attending.   All patients must 
meet all of the following inclusion criteria to be enrolled in the study: 
 
All patients must meet all of the following inclusion criteria to be enrolled in the study: 
 
• 
Patients 18 years or older. 
• 
Diagnosis: myeloid or lymphoid hematologic malignancy treated with a RI or NMA 
conditioning HSCT who received calcineurin inhibitor based drug (for example: tacrolimus 
or cyclosporin) and methotrexate as part of their initial GVHD prophylaxis . Patients who 
received sirolimus as part of their GVHD prophylaxis will be eligible. 
• 
Recipients of 8-7/8 HLA-matched donor. Post-HSCT period within day +100 to day +150. 
• 
Female patients who: 
o Are postmenopausal for at least 1 year before the screening visit, OR 
o Are surgically sterile, OR 
o If they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing the informed consent form 
through 90 days after the last dose of study drug, OR 
o Agree to practice true abstinence when this is in line with the preferred and usual 
lifestyle of the subject (periodic abstinence and withdrawal are not acceptable 
methods of contraception). 
• 
Male patients, even if surgically sterilized (i.e. Status post-vasectomy) must agree to one of 
the following: 
o Agree to practice effective barrier contraception during the entire study treatment 
period and through 90 days after the last dose of study drug, OR 
o Agree to practice true abstinence when this is in line with the preferred and usual 
lifestyle of the subject (periodic abstinence and withdrawal are not acceptable 
methods of contraception). 
 
Organ Function and Performance Status Criteria: 
• 
Karnofsky score > 70 % 
• 
Absolute neutrophil count (ANC) > 1000/mm3 and platelet count > 75,000/mm3. Platelet 
transfusions to help patients meet eligibility criteria are not allowed within 3 days before 
study enrollment. 
• 
Calculated creatinine clearance > 30 mL/min (based on the Cockcroft and Gault method) 
• 
Total bilirubin < 1.5 x upper limit of normal range (ULN). 
• 
AST/ALT < 3 x ULN (unless benign congenital hyperbilirubinemia). 
• 
Hemoglobin > 8.0 g/dL.  Red blood cell transfusions to help patients meet eligibility criteria 
are not allowed within 3 days before study enrollment. 
 
6.3 
Subject Exclusion Criteria 
 
• 
Disease: evidence of  progressive disease at the time of study enrollment. 
• 
Prior Therapy: one or more prior allogeneic stem cell transplantation (prior autologous 
transplant is acceptable). 
• 
Active acute or chronic GVHD. 
• 
Active and uncontrolled infection. 
• 
Pregnant or breast feeding. 
• 
Major surgery within 14 days before enrollment. 


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• 
Evidence of current uncontrolled cardiovascular conditions, including uncontrolled 
hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, 
unstable angina, or myocardial infarction within the past 6 months. 
• 
Systemic treatment, within 14 days before the first dose of ixazomib, with strong inhibitors 
of 
CYP1A2 
(fluvoxamine, 
enoxacin, 
ciprofloxacin), 
strong inhibitors of 
CYP3A 
(clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, 
posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, 
phenytoin, phenobarbital), or use of Ginkgo biloba or St. John’s wort. 
• 
Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol. 
• 
Patient or guardian unable to give informed consent or unable to comply with the treatm ent 
protocol including appropriate supportive care, follow-up and research tests. 
• 
Patients with known allergy to boron or boron-containing products, or excipients in the 
various formulations of any agent. 
• 
Known GI disease or GI procedure that could interfere with the oral absorption or tolerance 
of ixazomib including difficulty swallowing. 
• 
Diagnosed or treated for another malignancy within 2 years before study enrollment or 
previously diagnosed with another malignancy and have any evidence of residual 
disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not 
excluded if they have undergone complete resection. 
• 
Patient with  Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical 
examination during the screening period. 
• 
Received post-transplant cyclophosphamide 
 
7.0 
RECRUITMENT PLAN 
 
Patients who meet the eligibility criteria as listed in Section 6.0 will be recruited for this study 
by an Attending Physician of the Adult BMT service. This protocol will take due notice of 
NIH/ADAMHA policies concerning inclusion of women and minorities in clinical research 
populations. 
 
8.1 
PRETREATMENT EVALUATION 
 
8.1 
Pretreatment evaluation 
 
The following tests must be performed prior to study drug treatment starts.   Tests that are 
performed within 30 days prior to consent are not required to be repeated: 
• 
Complete history, review of systems, physical exam (including performance status) 
• 
CBC with differential, comprehensive metabolic panel (CMP), thyroid function test (TSH 
and free T4) 
• 
EKG 
• 
Urinalysis 
• 
Pregnancy test (required only for females of childbearing age) 
• 
Immune function tests (testing is performed following institutional practice and is 
recommended before starting treatment with ixazomib) 
 
9.1 
TREATMENT/INTERVENTION PLAN 


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Patients will be cared and monitor according to he allogeneic BMT clinical care guidelines.  
https://one.mskcc.org/sites/pub/corp/bmt/Documents/H3_Allo%20Guidelines_01_27_2016.p   df   
Patients will have received a calcineurin inhibitor based GVHD prophylaxis with either 
tacrolimus or cyclosporin in combination with methotrexate. The study drug will be initiated 
between day 100 to 150 post-allograft. 
Tapering of calcineurin inhibitor (CNI) will follow the institutional practice. For recipients of 
HLA-matched sibling donor, is recommended to initiate CNI taper around day 100 and taper 
at 10-25% decrements every 2 weeks.  For recipients of HLA-matched unrelated and HLA- 
mismatched unrelated donors, is recommended to initiate CNI taper around day 180 and 
taper at 10-15% decrements in 4 weeks intervals. 
9.2 
GVHD prophylaxis 
 
Ixazomib beginning between day +100 to +150 at a dose of 4 mg orally once per week (3 
weeks on/ 1 week off). The patients will continue on this same dose until taper off from 
immunosupressants or 1 year post-HSCT is reached (whichever occurs first) or until the 
patient develops GVHD or malignant disease  relapse/progression  occurs.  Patients  who 
reach 1 year post-HSCT or discontinue immunosuppressants mid-cycle should complete 
their current cycle of ixazomib. 
o The levels of the drug will not be monitored while the patients are on study. 
o In order for patients  to receive drug, they must have a platelet count > 75K, Hgb 
(untransfused) > 8 and an ANC > 1.0 (can be supported with G-CSF) 
o If more than 2 doses in a row or more than 3 doses total are held, the patient is 
removed from study. 
o Doses are given weekly +/- 3 days 
 
9.1.1 Dose-modification guidelines 
 
Treatment with ixazomib will use a cycle length of 28 days. For a new cycle of treatment to 
begin, the patient must meet the following criteria: 
 
o ANC > 1,000/mm3 
o Platelet count > 75,000/mm3 
o Serum creatinine ≤ 2.5 mg/dL and less than double from  pre-treatment evaluation 
value 
 
If the patient fails to meet the above-cited criteria for initiation of the next cycle of treatment, 
dosing should be delayed for 1 week. At the end of that time, the patient should be re- 
evaluated to determine whether the criteria have been met. If the patient continues to fail to 
meet the above-cited criteria, delay therapy and continue to re evaluate. The maximum delay 
before treatment should be discontinued will be 4 weeks or at the discretion of the Principal 
Investigator. 
 
Ixazomib dose adjustments: 
 
Dose Level 
Dose (mg) 
Starting Dose 
4.0 mg 
-1 
3.0 mg 
-2 
2.3 mg 


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-3 
Discontinue 
 
 
 
 
Table 9.1.1 Ixazomib dose adjustments for hematologic toxicities 
 
Criteria 
Action 
W ithin-Cycle Dose Modifications 
• 
If platelet count  30  10
9/L or ANC ≤ 
0.50  109/L on ixazomib dosing day 
(other than Day 1) 
• 
If serum creatinine > 2.5 mg/dL or has 
doubled from pre-treatment evaluation 
• 
Ixazomib dose should be withheld. 
• 
Complete blood count (CBC) with 
differential should be repeated until the 
ANC and/or platelet counts have 
exceeded the prespecified values. 
• 
Upon recovery, ixazomib may be 
reinitiated with 1 dose level reduction. 
Dose Modifications for Subsequent 
Treatment Cycles 
• 
Delay of > 2 weeks in the start of a 
subsequent cycle due to lack of toxicity 
recovery as defined in Section 9.1.1 
• 
ANC < 1.0  109/L, platelet count < 75 
 109/L, serum creatinine > 2.5 mg/dL, 
serum creatinine doubled from pre- 
treatment evaluation, or other 
nonhematologic toxicities > Grade 1 or 
not to the patient’s baseline condition 
• 
Hold ixazomib until resolution as per 
criteria Section 9.1.1 
• 
Upon recovery, reduce ixazomib 1 dose 
level. 
• 
The maximum delay before treatment 
should be discontinued will be 3 weeks 
or at the discretion of the PI. 
Dose Modifications for Subsequent 
Treatment Cycles 
• 
All hematologic toxicities 
• 
For hematologic toxicity that occurs 
during a cycle but recover in time for 
the start of the next cycle,: 
o If dose was reduced within 
the cycle, start the next cycle 
at that same dose. 
o If due to toxicity timing, i.e. 
after Day 15 dosing thus a 
dose reduction was not 
required at that point in the 
cycle, reduce ixazomib by 1 
dose level at the start of that 
cycle. 
o Do not reduce the dose both 
within a cycle and at the 
start of the cycle for the 
same most severe toxicity. 
 
 
9.1.2. Excluded concomitant medications and procedures 


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The following medications and procedures are prohibited during the study. 
Systemic treatment with any of the following metabolizing enzyme inhibitors is not permitted 
in this study. A DDI with a strong inhibitor would increase the ixazomib exposure and could 
lead to a higher probability of an AE: 
o Strong inhibitors of CYP1A2: fluvoxamine, enoxacin, ciprofloxacin 
o Strong inhibitors of CYP3A: clarithromycin, telithromycin, itraconazole, voriconazole, 
ketoconazole, nefazodone, and posaconazole. 
 
Systemic treatment with any of the following metabolizing enzyme inducers should be 
avoided, unless there is no appropriate alternative medication for the patient’s use (rationale: 
Unlike with inhibitors, if there were to be a DDI with an inducer, ixazomib exposure would be 
less; therefore, there would be a reduced chance of an AE. However, there may be less 
chance for an antitumor effect, but that is not an absolute reason to be taken off ixazomib): 
o Strong CYP3A inducers: rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, 
and phenobarbital. 
o Exclude foods and dietary supplements include St. John’s wort and Ginkgo biloba. 
The following procedures are prohibited during the study: 
o The addition of immunosuppresant(s) and/or GVHD prophylactic agents once 
enrolled in the study. 
o Platelet transfusions to help patient meet eligibility platelet level criteria are not 
allowed within 3 days prior to study drug dosing for any dosing day. 
 
9.1.3. Precautions and restrictions 
Fluid deficit should be corrected before initiation of treatment and during treatment. 
Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided with impaired renal 
function given reported NSAID-induced kidney injury in patients with decreased renal 
function. 
 
9.2 
Management of clinical events 
 
Adverse drug reactions such as thrombocytopenia, diarrhea, fatigue, nausea, vomiting, and 
rash have been associated with  ixazomib  treatment.  Management  guidelines  regarding 
these events are outlined below. Further details of management of ixazomib AEs are 
described in Section 9.1.1 
9.2.1    Nausea and/or vomiting 
 
Standard anti-emetics including 5-hydroxytryptamine 3 serotonin receptor antagonists are 
recommended for emesis if it occurs once treatment is initiated; prophylactic anti-emetics 
may also be considered at the physician’s discretion. Dexamethasone should not be 
administered as an anti-emetic. Fluid deficit should be corrected before initiation of study 
drug and during treatment. 
9..2.2 Diarrhea 
 
Prophylactic antidiarrheals will not be used in this protocol. However, diarrhea should be 
managed according to clinical practice, including the administration of antidiarrheals once 
infectious causes are excluded. If GVHD is suspect, proper evaluation including endoscopic 
evaluation with biopsy should be conducted. Fluid intake should be maintained to avoid 
dehydration. Fluid deficit should be corrected before initiation of treatment and during 
treatment. 


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9.2.3 Erythematous rash with or without pruritus 
 
As with bortezomib, rash with or without pruritus has been reported with ixazomib, primarily 
at the higher doses tested and when given with agents where rash is an overlapping toxicity. 
The rash may range from limited erythematous areas, macular and/or small papular bumps 
that may or may not be pruritic over a few areas of the body, to a more generalized eruption 
that is predominately on the trunk or extremities. Rash has been most commonly 
characterized as  maculopapular or macular. To date, when it does occur, rash is  most 
commonly reported within the first 3 cycles of therapy. The rash is often transient, self- 
limiting, and is typically Grade 1 to 2 in severity. 
 
Symptomatic measures such as antihistamines or corticosteroids (oral or topical) have been 
successfully used to manage rash and have been used  prophylactically  in  subsequent 
cycles. The  use of a  topical, IV, or oral  steroid  (e.g., prednisone  ≤ 10  mg  per day or 
equivalent) is permitted. Management of a Grade 3 rash may require intravenous 
antihistamines or corticosteroids. Administration of ixazomib (and/or other causative agent if 
given in combination) should be modified per protocol and re-initiated at a reduced level from 
where rash was noted. 
In line with clinical practice, dermatology consult and biopsy of Grade 3 or higher rash or any 
SAE involving rash is recommended. Prophylactic measures should also be considered if a 
patient has previously developed a rash (e.g. using a thick, alcohol-free emollient cream on 
dry areas of the body or oral or topical antihistamines). A rare risk  is Stevens -Johnson 
Syndrome, a severe and potentially life-threatening rash with skin peeling and mouth sores, 
which should be managed symptomatically according to standard medical practice. Punch 
biopsies for histopathological analysis are encouraged at the discretion of the investigator. 
9.2.4 Neutropenia and thrombocytopenia 
 
Blood counts should be monitored regularly as outlined in the protocol with additional testing 
obtained according to standard clinical practice. Growth factor support is not required but 
may be considered according to standard clinical practice. Ixazomib administration should be 
modified as noted as per dose modification recommendations in the protocol when 
neutropenia occurs (see Table 9.1.1). Therapy can be reinitiated at a reduced level upon 
recovery of neutropenia. 
 
Thrombocytopenia may be severe but has been manageable with platelet transfusions 
according to standard clinical practice. Ixazomib administration should be modified as noted 
as per dose modification recommendations in the protocol when thrombocytopenia occurs. 
Therapy can be reinitiated at a reduced level upon recovery of platelet counts. A rare risk is 
thrombotic thrombocytopenic purpura (TTP), a rare blood disorder where blood clots form in 
small blood vessels throughout the body characterized  by  thrombocytopenia,  petechiae, 
fever, or possibly more serious signs and symptoms. TTP should be managed 
symptomatically according to standard medical practice. 
9.2.5 Fluid deficit 


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Dehydration should be avoided since ixazomib may cause vomiting, diarrhea, and 
dehydration. Acute renal failure has been reported in patients treated with ixazomib, 
commonly in the setting of the previously noted gastrointestinal toxicities and dehydration. 
 
Fluid deficit should be corrected before initiation of study drug and as needed during 
treatment to avoid dehydration. 
9.2.6 Hypotension 
 
Symptomatic hypotension and orthostatic hypotension with or without syncope have been 
reported with ixazomib. Blood pressure should be closely monitored while the patient is on 
study treatment and fluid deficit should be corrected as needed, especially in the setting of 
concomitant symptoms such as nausea, vomiting, diarrhea, or anorexia. Patients taking 
medications and/or diuretics to manage their blood pressure, should be managed according 
to standard clinical practice, including considerations for  dose  adjustment  of  their 
concomitant medications during the course of the trial. Fluid deficit should  be  corrected 
before initiation of study as needed during treatment to avoid dehydration. 
9.2.7 Posterior reversible encephalopathy syndrome 
 
One case of posterior reversible encephalopathy syndrome, which ultimately resolved, has 
been reported with ixazomib. This condition is characterized by headache, seizures and 
visual loss, as well as abrupt increase in blood pressure. Diagnosis may be confirmed by 
magnetic resonance imaging (MRI). If the syndrome is diagnosed or suspected, symptom- 
directed treatment should be maintained until the condition is reversed by control of 
hypertension or other instigating factors. 
9.2.8 Transverse myelitis 
 
Transverse myelitis has also been reported with ixazomib. It is not known if ixazomib causes 
transverse myelitis; however, because it happened to a patient receiving ixazomib, the 
possibility that this drug may have contributed to transverse myelitis cannot be excluded. 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
All patients will be closely monitored and evaluated as per MSKCC BMT standard of care 
guidelines. Study specific assessment schedule listed in table below. 
 
Evaluation includes history and physical examination, blood count, chemistry including liver 
function test at screening, 6 months and 12 months post-allograft. Blood counts and blood 
chemistries will be monitored before the initiation of each treatment cycle and prior to the 
third dose of cycles 1 and 2. 
Toxicity assessment will be performed monthly during the duration of treatment or 
discontinuation of the study drug.  Prior to initiating the first two cycles, toxicity assessments 
will be performed at MSKCC’s main campus when feasible.  Toxicity assessments for 
subsequent cycles can be collected via phone call. 


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Acute and chronic GVHD will be diagnosed and graded according to established criteria5,25. 
Assessments will be obtained at approximately at day 100, 6 months, and 12 months. 
Additional time points will be done if clinically indicated. 


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Scheduled Study Assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 CBC and Chemistry are required prior to dose 1 and dose 3 for the first 2 cycles and then prior to first dose of each 
subsequent drug cycle 
2 Thyroid function test should include thyroid stimulating hormone (TSH) and free T4 
3 Immune function testing is performed per institutional practice and is recommended at indicated study time points. 
4 To be collected prior to first dose of each cycle. 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
11.1 Toxicity Grading 
Toxicities will be graded on a scale of 0 to 4 as described by the NCI- Common Terminology 
for Adverse Events (CTCAE), version 4.0. 
 
11.2 
Ixazomib 
lxazomib may cause fatigue, thrombocytopenia, nausea, vomiting, diarrhea, decreased 
appetite. Less frequently the drug can cause rash, peripheral edema,  and  neutropenia. 
Further details of management of ixazomib-related hematologic toxicity AEs are described in 
Section 9.1.1. 
Treatment modifications due to ixazomib-related AEs are outlined in Table 11.2. 
Study time-points 
Procedures 
Consent 
Pre- 
Treatment 
Evaluation 
Ixazomib 
Cycles 1- 
9 
6 
months 
post- 
HSCT 
12 
months 
post- 
HSCT 
Safety 
Follow 
Up 
Window 
100 – 150 
days 
post- 
HSCT 
- 30 days 
prior to 
Dose 1 
+/- 3 days 
+/- 14 
days 
+/- 30 
days 
30 days 
after last 
treatment 
+/- 7 
days 
Informed consent 
X 
History/ Physical 
X 
X 
X 
Karnofsky score 
X 
CBC1 
X 
X 
Blood Chemistry/ CMP1 
X 
X 
X 
X 
Thyroid function test2 
X 
X 
X 
EKG 
X 
Pregnancy test (if 
applicable) 
X 
Urinalysis 
X 
Immune function testing3 
X 
X 
X 
GVHD evaluation 
X 
X 
X 
Toxicity assessment4 
X 
X 
X 
X 
X 


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Table 11.2 
Ixazomib treatment modification (delays, reductions, and 
discontinuations) due to adverse events (non-hematologic toxicities) 
Adverse Event (Severity) 
Action on Study Drug 
CTCAE Description 
Peripheral Sensory 
Neuropathy: 
Grade 1 peripheral sensory 
neuropathy 
• No action 
Grade 1: Asymptomatic; loss 
of deep tendon reflexes or 
paresthesia 
Grade 2 peripheral sensory 
neuropathy 
• Hold study drug until 
resolution to Grade ≤ 1 or 
baseline 
• Once recovered, resume 
study drug at same dose 
Grade 2: Moderate 
symptoms; limiting 
instrumental ADL 
Grade 3 peripheral sensory 
neuropathy 
• Hold study drug until 
resolution to Grade ≤ 1 or 
baseline 
• Reduce study drug to 
next lower dose upon 
recovery 
Grade 3: Severe symptoms; 
limiting self care ADL 
Grade 4 peripheral sensory 
neuropathy 
• Discontinue study drug 
Grade 4: Life-threatening 
consequences; urgent 
intervention indicated 
Nervous System Disorder: 
Grade 1 nervous system 
toxicity judged to be related 
to study drug 
Grade 2 nervous system 
toxicity judged to be related 
to study drug 
New or worsening grade 2 or 
grade 3 or 4 toxicity judged 
to be related to study drug 
• 
No action 
• 
Hold study drug until 
resolution to Grade ≤ 1 
or baseline 
• Discontinue study drug 
Grade 1: Asymptomatic or 
mild symptoms; clinical or 
diagnostic observations only; 
intervention not indicated 
Grade 2: Moderate; minimal, 
local or noninvasive 
intervention indicated; 
limiting age appropriate 
instrumental ADL 
Grade 3: Severe or 
medically significant 
but not immediately life- 
threatening; 
hospitalization or 
prolongation of existing 
hospitalization indicated; 
disabling; limiting self care 
ADL 


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IRB Number: 16-076 A(4) 
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Page 24 of 36 
 
 
 
 
 
Table 11.2 
Ixazomib treatment modification (delays, reductions, and 
discontinuations) due to adverse events (non-hematologic toxicities) 
 
Adverse Event (Severity) 
Action on Study Drug 
CTCAE Description 
Grade 4: Life-threatening 
consequences; urgent 
intervention indicated 
Grade 2 Rash 
• 
Symptomatic 
recommendations.  The 
investigator and project 
clinician may discuss 
considerations for dose 
modifications and 
symptom management. 
Grade 2: Rash covering 10- 
30% BSA with or without 
symptoms; limiting 
instrumental ADL 
Grade ≥ 3 nonhematologic 
toxicity judged to be related 
to study drug 
• Hold study drug until 
resolution to Grade ≤ 1 or 
baseline 
• Reduce study drug to 
next lower dose upon 
recovery 
If not recovered to 
Grade ≤ 1 or 
baseline within 4 
weeks 
• Discontinue treatment 
 
 
 
 
12.1 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
 
12.2 Criteria for therapeutic response for the primary endpoint 
The primary aim is to assess the efficacy of ixazomib for the prevention of recurrent or late 
grade II-IV aGVHD or chronic GVHD by 1-year post-transplant. Therapeutic response will be 
determined by the absence of grade II-IV aGVHD or chronic GVHD diagnostic features (or 
any of the other failure criteria listed in 12.2) during the study window 
 
Patients who receive at least one cycle of therapy will be considered evaluable for the 
primary endpoint. 
 
 
12.3 Criteria for treatment failure for the primary endpoint 
o Study drug is discontinued and unable to resume due to drug related toxicity. 
o New onset or recurrence of grade II-IV aGVHD (including GVHD flares). 
o New onset of chronic GVHD. 
o Administration of systemic therapy for treatment of GVHD. 
o Development of secondary graft failure during the administration of the study drug. 
o Mortality (transplant or treatment-related) 


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If treatment failure criteria is met, the patient will be removed from the study. A 30-day follow-up 
will be conducted for end-of-treatment evaluation for toxicity assessment. This follow-up may be 
conducted via phone call or in-person by the clinical team. 
12.4 Outcome assessment 
12.3.1 Graft-versus-host disease (GVHD) 
 
Acute GVHD will be diagnosed clinically and histological assessment will be obtained where 
possible. Grading of aGVHD will be based on IBMTR criteria25. Acute GVHD will be 
assessed at Day 100 at a consensus review. Recurrent aGVHD will be defined as the 
reappearance of aGVHD symptoms after day 100 whereas late acute GVHD will be defined 
as aGVHD occurring after day 100. Chronic GVHD will be diagnosed and graded according 
to consensus criteria5. Patients will be assessed for development of GVHD at 6 months and 
12 months post-allograft. Assessments will evaluate the severity of symptoms and signs 
caused by GVHD and possible confounding factors. Additional assessments may be 
conducted if clinically indicated. 
12.3.2 Secondary graft failure 
 
Secondary graft failure is loss of ANC to < 500/µL for 14 consecutive days after initial 
recovery or loss of donor chimerism to < 10% donor after primary donor engraftment has 
been achieved not due to progressive malignancy within the marrow. 
Patients with suspected graft failure will be evaluated with bone marrow biopsy to assess BM 
cellularity and assess for residual or recurrent disease, and molecular analyses of marrow. 
 
12.3.3 Transplant related mortality (TRM) 
TRM is defined as death at any time from the commencement of the study trial due to any 
cause other than disease relapse with the exception of automobile or other accidents. The 
incidence of TRM from the enrollment on protocol to 1 year after HSCT is a secondary end- 
point of the study. 
12.3.4 Disease progression 
 
Relapse of malignancy or progression of disease from the base-line documented pre-HSCT, 
is a secondary endpoint of this study and will be defined by an increasing number  of 
malignant cells  of recipient origin in the marrow over 5%, by the presence of circulating 
malignant cells, pathologic lymphadenopathy or by the presence of malignant cells at any 
other site. Radiologic studies, flow cytometric analysis or molecular studies of the marrow 
and/or peripheral blood, and/or biopsy of lymph nodes or other sites may also be obtained for 
the diagnosis of relapse or disease progression. 
12.3.5 Immunologic recovery and immunization 
Immune recovery will be performed at serial time points after transplant per standard of care 
as indicated in section 10. All time points will guide clinical decisions and be billable unless 
they are collected after a patient has completed immune recovery as marked by the initiation 
of vaccinations. Patients may be re-immunized from 12 months post-transplant according to 
the CDC guidelines. Percentage of patients who get vaccines on time and response to 
vaccination will be documented. 


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Patients who meet criteria for immunization (CD4 T cell > 200cells/µL, CD19 B cells > 50 
cells/µL, IgG > 500 mg/dl, > 8 weeks after last dose of IVIG, > 6 months after last dose of 
Rituximab) will have pre-immunization titers measured and will be immunized according to 
institutional guidelines. Post-vaccine titers will be obtained to evaluate for vaccination 
response which is defined as at least a fourfold rise in specific antibody levels or a rise to a 
level considered protective per standard BMT practice. 
 
12.3.6 Overall and progression-free survival 
Overall survival is defined as the time of study enrolled to death from any cause; patients 
who remain alive will be censored at the time of last follow-up. Progression-free survival is 
defined as time from study enrollment to death or disease progression. 
 
12.3.7 Percentage of patients who remain on immunosuppression 
We will score patients as remaining on immunosuppression at 1 year if they remain on 
immunosuppressants at 1 year after the date of their stem cell infusion. 
 
 
13.0     CRITERIA FOR REMOVAL FROM STUDY 
 
Patients will be removed from study if any of the following events occurs: 
• 
If at any time the patient is found to be ineligible for the protocol as designated in the 
section on Criteria Subject Eligibility, the patient will be removed from the study. 
• 
If subject withdraws consent for continued participation. Management will depend on 
where they are in their treatment course. Such patients will receive appropriate 
supportive care. 
• 
Grade II-IV acute GVHD or chronic GVHD develops. If a patient is in the middle of a 
cycle, the patient may finish their cycle and then will be removed from study. 
• 
Malignant disease relapse, progression, or death occurs. 
• 
If a patient experiences severe unexpected adverse events, the treating physician or 
primary investigator can remove the patient from study at their discretion. 
 
14.0 
BIOSTATISTICS 
 
This is a single arm phase 2 trial to investigate the efficacy of a weekly ixazomib regimen to 
reduce recurrent or late onset acute and chronic GVHD.  The primary endpoint of this study 
is the incidence of recurrent or late acute grade II-IV aGVHD or chronic GVHD from the time 
of enrollment (day +100 to +150) to 1-year post-transplant time point. In addition to GVHD, 
the additional treatment failure criteria listed in 12.2 are considered as   failures for the 
primary endpoint. Patients are evaluable for the primary endpoint if they complete at least 
one cycle of therapy. Patients who discontinue therapy prior to completing one cycle therapy 
for reasons unrelated to toxicity will be replaced. Patients who prematurely discontinue 
therapy after completing at least one cycle of therapy will  remain evaluable for the primary 
endpoint. 
The historical benchmark for this study is based on patients enrolled on MSK protocol 06- 
150. With these data, the estimated grade II-IV acute or chronic GVHD at 1-yr post- 
transplant among patients who could have been eligible to enroll on this study is 63% (no 


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Page 27 of 36 
 
 
 
 
patient died for reasons unrelated to GVHD). Therefore, the trial is designed such that a one- 
year incidence of recurrent or late acute grade II-IV GVHD or cGVHD of 40% would be 
considered promising for further development, whereas a 60% incidence would not be 
considered worthy of further study.  Using these thresholds, we will utilize a Simon’s two- 
stage optimal design based on the proportion of patients who develop GVHD. If more than  
10 of the initial 18 patients have recurrent or late acute grade  II to IV or cGVHD, the trial 
will terminate early due to lack of efficacy.   Otherwise, the trial will continue to the 
maximum sample size of 46. If at the end of the study at least 23 out of 46 patients are free 
of recurrent or late acute grade II-IV GVHD or cGVHD  the intervention will be considered 
promising for further development. The type I and type II errors are both set at 0.10. 
In order to reduce patient ris k, the study design includes early termination in the event of 
excessive graft failure or treatment-related mortality during the study period. Stopping 
rules for excessive failure and corresponding power calculations are given below. The 
calculations are based on marginal probabilities. 
 
Failure type 
Number of failures needed 
to suspend the study 
Failure rate in 
the population 
Probability boundary 
is crossed 
Secondary 
graft failure 
2 in the first 20 
0.02 
0.1 
3 at any point 
0.15 
0.98 
Transplant- 
related 1 yr. 
mortality 
4 in the first 10 
0.10 
0.07 
5 in the first 20 
7 in the first 30 
8 in the first 40 
0.30 
0.96 
9 at any point 
 
In addition to the primary objective, there are a number of secondary and safety endpoints 
included in this study: 
Secondary endpoints: 
 
1. Cumulative incidence of   cGVHD following study enrollment will be estimated. This will be 
calculated overall and by severity (moderate/severe). Disease progression and death in the 
absence of cGVHD are considered competing risks for this analysis. 
2. The cumulative incidence  of TRM from the time of study enrollment will be estimated, 
treating disease progression as a competing risk. 
3. The cumulative incidence of disease progression from the time of study enrollment will be 
estimated, treating death in the absence of disease progression as a competing event. 
4. The cumulative incidence of grade II-IV and III-IV acute GVHD will be estimated. Disease 
progression and death in the absence of acute GVHD are considered competing risks for this 
analysis. 
5. Kaplan-Meier methods will estimate overall and progression-free survival  from the time of 
study enrollment. 
6. The proportion of patients who are able to discontinue all immunosuppressive medication at 
one year will be estimated along with a 95% confidence interval. 
7. Graphical and summary measures will be used to describe CD3+CD4+ and CD3+CD8+ 
populations during the study window. 


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Exploratory Endpoint: 
1. The proportion of patients who are able to get vaccines on time will be report with an exact 
95% confidence interval. The vaccine response will be similarly described. Both timing and 
response will be estimated separately for each vaccine. 
 
2.  The treatment failure endpoint will be described separately for patients who enroll on study 
day +100 to day +125 and for patients who enroll on study day +125 to day +150. 
 
Safety Endpoint: 
1.   The frequency and severity of adverse events will be tabulated. 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain 
informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. During the registration process registering individuals will be required to 
complete a protocol specific Eligibility Checklist. The individual signing the Eligibility Checklist 
is confirming whether or not the participant is eligible to enroll in the study. Study staff are 
responsible for ensuring that all institutional requirements necessary to enroll a participant to 
the study have been completed. See related Clinical Research Policy and Procedure #401 
(Protocol Participant Registration). 
 
 
15.3 
Randomization 
 
This research study does not require randomization procedures. 
 
16.1 
DAT A M ANAGEMENT ISSUES 
 
Research Study Assistant (RSA) will be assigned to the study at MSKCC. The 
responsibilities of the RSA include project compliance, data collection, abstraction and entry, 
data reporting, regulatory monitoring, problem resolution and prioritization, and coordination 
of the activities of the protocol study team. 
 
The data collected for this study will be entered into a secure database Clinical Research 
Database (CRDB). Source documentation will be available to support the computerized 
patient record. 
16.2 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness 
of registration data. Routine data quality reports will be generated to assess missing data 
and inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will 
be monitored periodically throughout the study period and potential problems will be brought 
to the attention of the study team for discussion and action. 


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Random-sample data quality and protocol compliance audits will be conducted by the study 
team, at a minimum of two times per year, more frequently if indicated. 
16.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring Plans (DSM) at Memorial Sloan Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled “Policy of  the National Cancer 
Institute  for  Data  and  Safety  Monitoring  of  Clinical  Trials”  which  can  be  found  at:  
Http://cancertrials.nci.nih.gov/r esearchers/dsm/index.html. The DSM Plans  at  MSKCC were 
established and are monitored by the Clinical Research Administration. The MSKCC Data 
and 
Safety 
Monitoring 
Plans 
can 
be 
found 
on 
the 
MSKCC 
Intranet 
at:  
https://one.mskcc.org/sites/pub/clinresearch/Documents/MSKCC%20Data%20and%20Safet   
y% 
 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research QA) and departmental procedures for quality control, plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required.  Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed, 
and the monitoring procedures will be established at the time of protocol activation. 
17.1 
PROTECTION OF HUMAN SUBJECTS 
 
17.2 
Privacy 
 
MSK’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
17.3 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 


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• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE reporting is required as soon as the participant signs consent and is registered.  SAE 
reporting is required for 30-days after the participant’s last investigational treatment or 
intervention. Any events that occur after the 30-day period and that are at least possibly 
related to protocol treatment must be reported. 
 
An SAE must be reported to the IRB/PB within 5 calendar days of the event. The IRB/PB 
requires a Clinical Research Database (CRDB) SAE report be submitted electronically to the 
SAE Office as follows:. 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to  
saegrade5@mskcc.org.  All other reports should be sent to saemskind@mskcc.org. 
 
For all other trials: Reports that include a Grade 5 SAE should be sent to  
saegrade5@mskcc.org.  All other reports should be sent to sae@mskcc.org. 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject’s name (generate the report with only initials if it will be sent outside of 
MSK) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
 
The PI’s signature and the date it was signed are required on the completed report. 


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Page 31 of 36 
 
 
 
 
For IND/IDE protocols: 
The CRDB AE report should be completed as above.  If appropriate, the report will be forwarded to 
the FDA by the SAE staff through the IND Office. Potentially serious toxicities are an expected part  
of transplant therapy. Adverse events (AEs) and serious adverse events (SAEs) will be captured and 
reported as outlined in the Departmental Standard Working Procedure titled “Adult Bone Marrow 
Transplant (BMT) Adverse Event (AE) and Serious Adverse Event (SAE) Guide”. In addition, the 
expected adverse events outlined in Table 11.2 will be captured. 
17.2.1 
 
AEs which are serious must be reported to Takeda Pharmaceuticals/ Millennium 
Pharmacovigilance (or designee) from the first dose of study drug through 30 days after 
administration of the last dost of ixazomib. Any SAE that occurs at any time after completion 
of ixazomib treatment or after the designated follow-up period that the sponsor-investigator 
and/or sub-investigator considers to be related to any study drug must be reported to Takeda 
Pharmaceuticals/ Millennium Pharmacovigilance (or designee).  In addition, new primary 
malignancies that occur during the follow-up periods must be reported, regardless of 
causality to study regimen, for a minimum of three years after the last dose of the 
investigational product, starting from the first dose of study drug. All new cases of primary 
malignancy must be reported to Takeda Pharmaceuticals/ Millennium Pharmacovigilance (or 
designee). 
 
 
17.3.2 Serious Adverse Event Definition 
 
Serious AE (SAE) means any untoward medical occurrence that at any dose: 
• 
Results in death. 
 
• 
Is life-threatening (refers to an AE in which the patient was 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). 
 
• 
Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph below on planned hospitalizations). 
 
• 
Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions). 
 
• 
Is a congenital anomaly/birth defect. 
 
• 
Is a medically important event.  This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious 
when, based on appropriate medical judgment, may jeopardize the patient, require 
medical or surgical intervention to prevent 1 of the outcomes listed above, or involves 


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Page 32 of 36 
 
 
 
 
suspected transmission via a medicinal product of an infectious agent.   Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse; any 
organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or nonpathogenic, is considered an infectious 
agent. 
 
Clarification should be made between a serious AE (SAE) and an AE that is considered 
severe in intensity (Grade 3 or 4), because the terms serious and severe are NOT 
synonymous.  The general term severe is often used to describe the intensity (severity) of a 
specific event; the event itself, however, may be of relatively minor medical significance 
(such as a Grade 3 headache).  This is NOT the same as serious, which is based on 
patient/event outcome or action criteria described above, and is usually associated with 
events that pose a threat to a patient’s life or ability to function.  A severe AE (Grade 3 or 4) 
does not necessarily need to be considered serious.  For example, a white blood cell count 
of 1000/mm3 to less than 2000 is considered Grade 3 (severe) but may not be considered 
serious.  Seriousness (not intensity) serves as a guide for defining regulatory reporting 
obligations. 
 
17.3.3 Procedures for Reporting Serious Adverse Events 
AEs may be spontaneously reported by the patient and/or in response to an open question 
from study personnel or revealed by observation, physical examination, or other diagnostic 
procedures.  Any clinically relevant deterioration in laboratory assessments or other clinical 
finding is considered an AE.  When possible, signs and symptoms indicating a common 
underlying pathology should be noted as one comprehensive event.  For serious AEs, the 
investigator must determine both the intensity of the event and the relationship of the event 
to study drug administration. For serious pretreatment events, the investigator must 
determine both the intensity of the event and the relationship of the event to study 
procedures. 
Planned hospital admissions or surgical procedures for an illness or disease that existed 
before the patient was enrolled in the trial are not to be considered AEs unless the condition 
deteriorated in an unexpected manner during the trial (e.g., surgery was performed earlier or 
later than planned).  All SAEs should be monitored until they are resolved or are clearly 
determined to be due to a patient’s stable or chronic condition or intercurrent illness(es). 
Since this is an investigator-initiated study, the principal investigator (Doris M. Ponce), also 
referred to as the sponsor-investigator, is responsible for reporting serious adverse events 
(SAEs) to any regulatory agency and to the sponsor- investigator’s EC or IRB. 


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Regardless of expectedness or causality, all SAEs (including serious pretreatment events) 
must also be reported in English to Takeda Pharmaceuticals/ Millennium Pharmacovigilance 
(or designee): 
Fatal and Life Threatening SAEs within 24 hours but no later than 5 calendar days of the 
sponsor-investigator’s observation or awareness of the event. 
All other serious (non-fatal/non life threatening) events within 5 calendar days of the 
sponsor-investigator’s observation or awareness of the event 
See below for contact information for the reporting of SAEs to Takeda Pharmaceuticals/ 
Millennium  Pharmacovigilance. 
The sponsor-investigator must fax or email the de-identified SAE Form per the timelines 
above.  A sample of an SAE Form will be provided. 
The SAE report must include at minimum: 
• 
Event term(s) 
• 
Serious criteria 
• 
Intensity of the event(s): Sponsor-investigator’s or sub-investigator’s 
determination.  Intensity for each SAE, including any lab abnormalities, will be 
determined by using the NCI CTCAE version specified in the protocol, as a guideline, 
whenever possible.  The criteria are available online at  
http://ctep.cancer.gov/reporting/ctc.html. 
 
• 
Causality of the event(s): Sponsor-investigator’s or sub-investigator’s determination 
of the relationship of the event(s) to study drug administration. 
 
Follow-up information on the SAE may be requested by Takeda Pharmaceuticals/ 
Millennium. 
Intensity for each SAE, including any lab abnormalities, will be determined by using the NCI 
CTCAE version used at the institution, as a guideline, whenever possible. The criteria are 
available online at http://ctep.cancer.gov/reporting/ctc.html. 
Relationship to all study drugs for each SAE will be determined by the investigator or sub- 
investigator by responding yes or no to the question: Is there a reasonable possibility that the 
AE is associated with the study drug(s)? 
Sponsor-investigator must also provide Takeda Pharmaceuticals/ Millennium 
Pharmacovigilance with a copy of all communications with applicable regulatory authorities 
related to the study product(s). 
 
 
SAE and Pregnancy Reporting Contact Information 
Fax Number: 1-800-963-6290 
Email:  TakedaOncoCases@cognizant.com 


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17.3.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
If a woman becomes pregnant or suspects that she is pregnant while participating in this 
study or within 90 days after the last dose, she must inform the investigator immediately and 
permanently discontinue study drug.  The sponsor-investigator must immediately fax a 
completed Pregnancy Form to the Takeda Pharmaceuticals/ Millennium Department of 
Pharmacovigilance or designee (see Section 8.2).  The pregnancy must be followed for the 
final pregnancy outcome. 
If a female partner of a male patient becomes pregnant during the male patient’s participation 
in this study, the sponsor-investigator must also immediately fax a completed Pregnancy 
Form to the Takeda Pharmaceuticals/ Millennium Department of Pharmacovigilance or 
designee (see Section 8.2).  Every effort should be made to follow the pregnancy for the final 
pregnancy outcome. 
Suggested Pregnancy Reporting Form: 
• 
Pregnancy Report Form (provided by Takeda Pharmaceuticals/ Millennium) 
 
17.3.5 Administrative Requirements 
17.2.5.1 Products  complaints 
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product.  Individuals who 
identify a potential product complaint situation should immediately contact MedComm 
Solutions (see below) and report the event.  Whenever possible, the associated product 
should be maintained in accordance with the label instructions pending further guidance from 
a Takeda Pharmaceuticals/ Millennium Quality representative. 
 
 
 
 
 
 
Product complaints in and of themselves are not AEs. If a product complaint results in an 
SAE, an SAE form should be completed and sent to Takeda Pharmaceuticals/ Millennium 
Pharmacovigilance (refer to Section 17.2.3). 
 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain  
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
For Product Complaints, 
call MedComm Solutions at 
877-674-3784 (877 MPI DRUG) 
(US and International) 


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1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
19.0 
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20.0 
APPENDICES 
 
N/A