Conditions: Amyloidosis Plasma Cell Myeloma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 87
Healthy volunteers: no

Brief summary:
This phase I/II trial studies the side effects and the best dose of cyclophosphamide when given together with ixazomib citrate and dexamethasone in treating patients with previously untreated symptomatic multiple myeloma or light chain amyloidosis. Drugs used in chemotherapy, such as cyclophosphamide and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Ixazomib citrate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving cyclophosphamide together with ixazomib citrate and dexamethasone may be a better treatment for multiple myeloma or light chain amyloidosis.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose of cyclophosphamide that can be combined with ixazomib citrate (ixazomib) and dexamethasone in patients with previously untreated symptomatic multiple myeloma (MM). (Phase I Cohort A) II. To determine the complete plus very good partial response rate (\>= VGPR) of ixazomib, used in combination with cyclophosphamide and dexamethasone in patients with previously untreated symptomatic MM. (Phase II Cohort A) III. To determine the hematologic response rate of ixazomib, used in combination with cyclophosphamide and dexamethasone in patients with previously untreated light chain amyloidosis. (Phase II Cohort B)

SECONDARY OBJECTIVES:

I. To determine the progression free survival and overall survival among patients with previously untreated symptomatic MM following treatment with ixazomib in combination with cyclophosphamide and dexamethasone followed by ixazomib maintenance till progression. (Cohort A) II. To determine the toxicities associated with ixazomib in combination with cyclophosphamide and dexamethasone in patients with previously untreated symptomatic MM. (Cohort A) III. To determine the organ response rate of ixazomib, used in combination with cyclophosphamide and dexamethasone in patients with previously untreated light chain amyloidosis. (Cohort B) IV. To determine the progression free survival and overall survival among patients with previously untreated light chain amyloidosis following treatment with ixazomib in combination with cyclophosphamide and dexamethasone followed by Ixazomib maintenance till progression. (Cohort B) V. To determine the toxicities associated with ixazomib in combination with cyclophosphamide and dexamethasone in patients with previously untreated light chain amyloidosis. (Cohort B)

TERTIARY OBJECTIVES:

I. To examine the pharmacokinetics of ixazomib when used in combination with cyclophosphamide and dexamethasone. (Cohort A) II. To assess the incidence of neurotoxicity using patient completed questionnaires. (Cohort A)

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

INDUCTION THERAPY: Patients receive ixazomib citrate orally (PO) on days 1, 8, and 15 and cyclophosphamide PO and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive ixazomib citrate PO on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3-6 months for 5 years.

Arms:
arm 1: INDUCTION THERAPY: Patients receive ixazomib citrate PO on days 1, 8, and 15 and cyclophosphamide PO and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive ixazomib citrate PO on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Cyclophosphamide intervention 2: Dexamethasone intervention 3: Ixazomib Citrate intervention 4: Laboratory Biomarker Analysis intervention 5: Pharmacological Study intervention 6: Quality-of-Life Assessment intervention 7: Questionnaire Administration
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Given PO intervention 4: Correlative studies intervention 5: Correlative studies intervention 6: Ancillary studies intervention 7: Ancillary studies

Protocol document:
Prot_SAP_000.pdf: 




 
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Index 
Schema 
  1.0 
Background 
  2.0 
Goals 
  3.0 
Patient Eligibility 
  4.0 
Test Schedule 
  5.0  
Grouping Factors  
  6.0 
Registration/Randomization Procedures 
  7.0 
Protocol Treatment 
  8.0 
Dosage Modification Based on Adverse Events  
  9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation   
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Budget 
20.0 
References 
  
Appendix I – Mayo Risk Stratification 
Appendix II – NYHA Classification 
Appendix III - Multiple Myeloma Diagnostic Criteria 
Appendix IV – Patient Medication Diary 
Appendix V – Patient Information Booklet and FACT-GOG Neurotoxicity questionnaire 
Appendix VI: Millennium pregnancy form  
Appendix VII: ECOG performance status 




 
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Schema (Cohort B; AL cohort) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If a patient is deemed ineligible or a cancel, please refer to Section 13 for follow-up information. 
 
1 Cycle length = 28 days
Induction  
Ixazomib + Cyclophosphamide + 
Dexamethasone X 12 cycles 1 
Registration 
Maintenance  
Ixazomib till disease progression1  
PD at any time 2 
Unacceptable adverse events 
 
       Event Monitoring (per section 18.0) 
Patient refusal 
Subsequent treatment for amyloidosis 


 
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1.0 
Background 
 
1.1 
Multiple Myeloma: Multiple myeloma is a malignancy of the differentiated plasma cells, 
that affect the older patient with a median age at onset of 65-70 years and a slight male 
predominance. Nearly 20,000 patients with myeloma are diagnosed in the United States 
each year, and despite considerable improvements in therapy remains incurable and 
uniformly fatal with a median overall survival of around 8 years. Recent improvements in 
therapies have significantly improved the survival outcomes, but given the inevitable 
relapses seen in these patients, new approaches to therapy are clearly needed. The highly 
effective drug combinations currently used are beset with a degree of toxicity that 
precludes long-term therapy and also can affect the quality of life metrics. Finally, some 
of these regimens require IV or subcutaneous administration, which can require frequent 
clinic, visits for patients. The highly effective multi-drug regimens currently in use 
typically include a proteasome inhibitor, either bortezomib given IV or SQ or carfilzomib 
given IV. 
 
1.2 
The ubiquitin proteasome pathway in multiple myeloma: The ubiquitin-proteasome 
pathway is critical to cellular homeostasis, playing a major role in maintaining 
appropriate levels of different proteins in the cell.1,2 The ubiquitin-proteasome system is 
responsible for the orderly degradation of cellular proteins involved in virtually all 
aspects of cell growth and proliferation. The pathway degrades proteins involved in cell 
cycle regulation, cell survival, and metastasis such as p53, p21, p27 and NFkB. Ubiquitin 
is a 9kd protein that is abundantly present in the cell and is highly evolutionary 
conserved. Cellular proteins that are marked for degradation gets polyubiquitinated; 
where C-terminal glycine residues of the ubiquitin molecules attach covalently to specific 
lysine residues on the protein molecule. This three step process sequentially involves the 
ubiquitin activating enzyme E1, an ubiquitin conjugating enzyme E2 and an ubiquitin 
ligase E3. The first ubiquitin molecule forms the nidus for additional ubiquitin molecules 
to be attached. Once, polyubiquitinated, the protein is targeted by the 26S proteasome for 
degradation, an active energy requiring process that maintains protein levels in the cell. 
The 26S proteasome in the mammalian cells consists of a core 20S catalytic complex and 
a 19S regulatory complex. It is a cylindrical structure with an outer ring composed of 7 
alpha subunits and an inner ring that is made up of seven beta subunits. The 20S catalytic 
portion has chymotryptic, tryptic and peptidylglutamyl like activities, with the catalytic 
sites located in the inner surface of the cylinder. The ubiquitinated protein is recognized 
by the 19S subunit, the ubiquitin tags are cleaved, and the protein is hydrolyzed by the 
proteasome at six different catalytic sites present in the 20S catalytic complex. In vitro 
studies in a variety of cancers demonstrate the ability of proteasome inhibitors to 
selectively target the malignant cells supporting this strategy for cancer therapy. The 
mechanism of selectivity is not clear, but may be related to increased dependency of 
rapidly proliferating cells on the pathway. Bortezomib was the first proteasome inhibitor 
to enter human trials.3 
 
In the setting of MM, several in vitro studies have shown the ability of proteasome 
inhibitors to inhibit proliferation and induce apoptosis of MM cell lines and freshly 
isolated patient MM cells as well as overcome adhesion mediated resistance.4 They can 
inhibit the paracrine growth of human MM cells by decreasing their adherence to bone 
marrow stromal cells (BMSCs) and related nuclear factor B-dependent induction of 
interleukin-6 secretion by BMSCs. The mechanism of anti-MM activity of proteasome 
inhibitors are likely multiple. Transcriptional profiling of MM cells treated with 
bortezomib, a proteasome inhibitor currently in the clinic, demonstrated down-regulation 


 
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of growth/survival signaling pathways, and up-regulation of molecules implicated in pro-
apoptotic cascades, as well as up-regulation of heat-shock proteins and 
ubiquitin/proteasome pathway members. In addition, treatment decreased the levels of 
several anti-apoptotic proteins and triggered the release of mitochondrial cytochrome c 
and caspase-9 activation, all contributing to apoptosis of MM cells. One of the key effects 
is thought to be the inhibition of the NFkB pathway, which is critical to the MM cell 
proliferation induced by growth factors as well as adhesion to BMSC. Other purported 
mechanisms include (i) activation of classical stress response proteins such as heat shock 
proteins, Hsp27, Hsp70, and Hsp90; (ii) up regulation of c-Jun-NH2-terminal kinase 
(JNK); (iii) activation of extrinsic apoptotic signaling through Bid and caspase-8 
cleavage; and (iv) inactivation of DNA-dependent protein kinase (DNA-PK), which is 
essential for the repair of DNA double-strand breaks. 
 
1.3 
Initial therapy of multiple myeloma: The treatment paradigms for multiple myeloma 
have undergone a significant change in the past decade.5,6 A decade ago, patients who 
were considered eligible for transplant underwent the procedure after a brief duration of 
therapy with a steroid based regimen with or without doxorubicin. Patients ineligible for 
transplant went on to receive melphalan and prednisone. With these treatment approaches 
patients had a median survival of 3-4 years, with nearly 10-20% of patients dying in the 
first year after diagnosis. During the last decade several new drugs were introduced such 
as thalidomide and its analogue lenalidomide and the proteasome inhibitor bortezomib 
and these along with continued use of transplant has led to improved survival in 
myeloma.7 In fact, in the recent clinical trials 3-year survival has approached 90% and 1-
year mortality has dropped to under 2%.8 This progress has come through a series of 
investigations examining the efficacy of the new drugs used in various combinations and 
sequences. Initial trials in the relapsed setting confirmed significant clinical activity for 
all these new drugs. This was followed by several clinical trials that examined the 
combination of novel agents with dexamethasone in the setting of newly diagnosed 
disease. The studies consistently demonstrated superior response rates, deeper responses, 
and improved progression-free survival for patients undergoing initial therapy with novel 
agents.8-11 The trials examined the role of the new drugs in the context of transplant 
eligible and ineligible patients. This has been followed by three drug regimens that either 
combined the new drugs together or incorporated an alkylator drug to the novel agent-
dexamethasone combination. These have included combinations of bortezomib and 
dexamethasone with thalidomide (VTD), lenalidomide (VRd) or cyclophosphamide 
(VCD).9,10,12,13 
 
Of particular interest are the VCd and VRd regimens, both of which have shown high 
efficacy rates and are increasingly used for initial therapy in the community.9,13 In a phase 
2 study, Reeder et al showed that initial therapy with bortezomib, cyclophosphamide and 
dexamethasone is associated with high rate of deep responses among patients with 
previously untreated myeloma, being considered for autologous stem cell transplantation. 
Similarly, VRd regimen has been associated with high response rates approaching 100% 
and deep responses with very good partial response rates and complete response rates of 
over 70 and 40% respectively. It has proven to be a highly effective initial therapy for 
patients planning stem cell transplantation with no significant effect on the ability to 
successfully mobilize stem cells.  
 
In the EVOLUTION trial, patients were randomized to receive bortezomib 1.3 mg/m2 d 
1, 4, 8, 11 and dexamethasone 40 mg d 1, 8, 15, with either cyclophosphamide 500 
mg/m2 d 1, 8 and lenalidomide 15 mg d 1–14 (VDCR), lenalidomide 25 mg d1-14 (VRd), 


 
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cyclophosphamide 500 mg/m2 d 1, 8 (VCD) or cyclophosphamide 500 mg/m2 d 1, 8, 15 
(VCD-mod) in a 21 day cycle (maximum 8 cycles).13,14 This was followed by bortezomib 
1.3 mg/m2 (d 1, 8, 15, 22) for four 42-day maintenance cycles in all arms. VGPR or better 
was seen in 58, 51, 41 and 53% (CR rate of 25, 24, 22 and 47%) of patients (VDCR, 
VRd, VCD 8-and VCD-mod arms, respectively); the corresponding progression-free 
survival (PFS) at 1 year was 86, 83, 93 and 100%, respectively. Common adverse events 
included hematological toxicities, peripheral neuropathy, fatigue, and GI disturbances. 
Overall no substantial advantage was noted with the addition of cyclophosphamide to 
VRd, but the regimen did lead to more hematological toxicities. An important outcome of 
this trial was the similar results obtained with the VRd and VCd regimens, especially 
considering the cost differential between the two regimens. 
 
 
1.4 
Light chain amyloidosis: Light chain amyloidosis is characterized by light chain 
secreting plasma cells in the bone marrow, usually in small numbers, but leading to 
formation and deposition of amyloid protein in different organs including the heart, 
kidneys and liver. While therapeutic options have improved over time and patients with 
AL are living longer, it remains incurable and patients invariably need additional 
therapeutic options. The median survival of patients with AL amyloidosis is 18-24 
months with nearly 40% dying within the first year of diagnosis. 1-4. Traditionally, 
therapies that have appeared to be promising for treatment of patients with myeloma have 
been studied in the context of amyloidosis, given the fundamental similarities in the 
disease.  
 
The combination of melphalan and prednisone has been in use for decades and results in 
approximately 20-30% of patients achieving a measurable response 5-7.  Several 
prospective randomized studies have demonstrated that chemotherapy-treated patients 
have a longer median survival than patients who do not receive chemotherapy 8-10.  The 
median survival of the melphalan- and prednisone (MP) treated group of patients in a 
phase III trial conducted at Mayo Clinic was 17 months compared to 8.5 months for those 
not receiving MP9. Even though this represented a significant improvement, the outcome 
still remained dismal and patients with significant cardiac disease had a median survival 
of only six months. Patients in this trial who achieved a reduction in their paraprotein 
level had a longer survival compared to those who did not highlighting the importance of 
hematologic response. A similar trial conducted at the Boston University resulted in 
similar improvements with Melphalan and prednisone10. Majority of patients fail to 
demonstrate objective evidence of disease regression and ultimately succumb to their 
disease.  
 
High dose therapy and melphalan with autologous peripheral blood stem cell 
transplantation has been used for treatment of amyloidosis, given its efficacy and survival 
advantage in patients with multiple myeloma 11-13.  Case controlled studies have 
demonstrated that high dose therapy improves survival in patients with amyloidosis who 
are eligible to go through the procedure 14. Stem cell transplant results in improvement 
in the organ function in over half of the patients who survive the process13. Many of 
these responses also tend to be durable. However, there remains considerable selection 
bias as case controlled studies have shown that patients eligible for a stem cell transplant 
have better overall performance status and are likely to do better than the average patient 
even with out stem cell transplant15. Moreover, this modality is not feasible in nearly two 
thirds of AL patients due to poor performance status and advanced organ involvement. 
The risk of mortality is considerable (20-40% in different series) and increases with the 


 
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degree of individual organ involvement as well as the number of organs involved. So 
alternative, effective and less toxic regimens are needed for the majority of patients with 
this disease. 
 
More recently, studies have highlighted the role of proteasome inhibitors in the treatment 
of AL amyloidosis. This agent is of particular importance given the ability to reduce 
immunoglobulin free light chain levels and the critical role of the free light chains in the 
amyloid pathophysiology. Bortezomib has been used in combination with dexamethasone 
alone or cyclophosphamide or melphalan along with dexamethasone.  Kastritis et al 
reported on 94 patients from three centers treated with bortezomib and dexamethasone, 
with nearly 80% of the patients with relapsed disease.16 A hematologic response was 
achieved in 71%, including 25% complete responses. Previously untreated patients had a 
47% CR rate. Hematologic responses were associated with a cardiac response and NT-
proBNP reduction. Toxicity was manageable and mostly consisted of neuropathy, 
orthostasis, peripheral edema, and constipation or diarrhea. Reece et al studied 31 
patients in a dose escalation study of bortezomib given weekly or twice weekly and 
observed hematologic responses in 50% of 30 evaluable patients, including 20% 
complete responses.17 More recently, Venner et al studied 43 patients treated with AL 
cyclophosphamide, bortezomib, and dexamethasone.18 The overall hematologic response 
rate was 81.4%, including complete response in 42% and very good partial in 51.4%. The 
estimated 2-year progression-free survival was 66.5% for patients treated upfront and 
41.4% for relapsed patients.  
 
Ixazomib is the first oral proteasome inhibitor introduced in the clinic, and is currently 
approved for use in relapsed myeloma. Ixazomib has been evaluated as an oral single 
agent in phase 1 studies that have included patients with advanced solid tumors, 
lymphoma, relapse/refractory MM (RRMM), and relapsed or refractory light-chain (AL) 
amyloidosis and demonstrated early signs of activity.19,20 Ixazomib has also been 
studied alone and in combination with dexamethasone in patients with relapsed disease 
not refractory to bortezomib. Thirty-three patients with relapsed multiple myeloma were 
treated with Ixazomib at 5.5 mg weekly for 3 of 4 weeks. Dexamethasone was added for 
lack of a minor response (MR) by end of cycle 2 or lack of a partial response (PR) by end 
of cycle 4 or for disease progression at any time. Median age was 69 years; patients had a 
median of two prior therapies (range 1-7). Dexamethasone was initiated in 22 (67%) 
patients, 17 for not reaching the desired response and 5 for progression. Response (⩾PR) 
to single agent was seen in five patients within four cycles of therapy including three 
patients with PR, one patient with complete response (CR) and one patient with stringent 
CR. Six additional patients with either an MR (2) or SD (4) achieved a PR after addition 
of dexamethasone, translating to an overall response rate of 34%. Ongoing studies 
continue to investigate both single-agent Ixazomib and Ixazomib in combination with 
standard treatments. A recently reported phase 3 trial of Ixazomib in combination with 
lenalidomide and dexamethasone in relapsed myeloma with 1-3 prior treatments 
demonstrated a significant improvement in PFS. Previously a phase 2 trial of the same 
combination in newly diagnosed myeloma was very effective with high rate of responses, 
deep responses and well tolerated with the ability to administer the drug long term.21 
Ixazomib also appear to combine well with cyclophosphamide and has been shown to be 
effective in relapsed and newly diagnosed myeloma.  
 
1.5 
IXAZOMIBIxazomib:    Ixazomib, which has been formulated for both intravenous (IV) 
and oral (PO) administration, is a small molecule proteasome inhibitor.  It is the citrate 
ester of the biologically active boronic acid form, MLN2238, which is structurally similar 


 
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to bortezomib.  In water or aqueous systems, Ixazomib rapidly hydrolyzes to MLN2238, 
therefore all doses and concentrations are expressed as MLN2238.  Nonclinical studies 
were conducted with a solution of either MLN2238 or MLN2238 in equilibrium with 
Ixazomib.  Similar to bortezomib, MLN2238 potently, reversibly, and selectively inhibits 
the 20S proteasome.  However in contrast to bortezomib, it has a shorter dissociation 
half-life (t1/2) that may contribute to increased tissue distribution.  Bortezomib has a 
slowly reversible dissociation rate from the red blood cell proteasome, while MLN2238 
demonstrates a more rapidly reversible dissociation rate from the blood but sustained 
effects on bone marrow and tumor proteasomes suggesting better tissue distribution.  The 
pharmacologic implications of this difference in binding kinetics and tissue distribution 
may in turn result in differences in safety and efficacy profiles in a broader range of 
tumors.  In xenograft-bearing mice, the more rapid dissociation rate correlates with an 
increased ratio of tumor proteasome inhibition to blood proteasome inhibition, and 
Ixazomib shows greater antitumor activity in several xenograft models, both solid tumor 
and bortezomib-resistant xenografts, than bortezomib.   
 
Nonclinical Pharmacology: MLN2238 refers to the biologically active, boronic acid form 
of the drug substance, Ixazomib.  Ixazomib refers to the citrate ester of MLN2238.  In 
water or aqueous systems, the equilibrium shifts from Ixazomib to the biologically active 
boronic acid form MLN2238.  All doses and concentrations are expressed as the boronic 
acid, MLN2238. 
 
In Vitro Pharmacology: MLN2238 preferentially binds the β5 site of the 20S proteasome; 
at higher concentrations, it also inhibits the activity of the β1 and β2 sites.  MLN2238 
inhibits ß5 site 20S proteasome activity in vitro, with a half-maximal inhibitory 
concentration (IC50) of 3.4 nM.  Potency is reduced roughly 10-fold versus ß1 (IC50  31 
nM) and 1,000-fold versus ß2 (IC50 =3500 nM).  MLN2238 was also tested for 
inhibition against a panel of 103 kinases, 18 receptors (neurotransmitter, ion channel, 
brain and gut receptors), and 9 serine proteases.  In all cases, the IC50 values were > 10 
μM.  MLN2238 and bortezomib have different β5 proteasome dissociation half-lives 
(t1/2), reflecting differences in their on-off binding kinetics (the β5 proteasome 
dissociation t1/2 for MLN2238 and bortezomib are 18 and 110 minutes, respectively).  
Based on these favorable characteristics, Ixazomib is anticipated to be effective against 
multiple myeloma. (Ixazomib Investigator’s Brochure (IB). Proteasome inhibition results 
in the accumulation of poly-ubiquitinated substrates within the cell and leads to cell cycle 
disruption, with concomitant activation of apoptotic pathways and cell death.  Consistent 
with inhibition of ß5 20S activity, MLN2238 demonstrated potent activity against 
cultured MDA-MB 231 human breast cancer cells in the WST cell viability assay.  In 
nonclinical models MLN2238 has activity against both solid tumor and bortezomib-
resistant xenografts 
 
In Vivo Pharmacology: To determine the activity of MLN2238 in vivo, 
pharmacodynamic studies were performed in immunocompromised mice bearing either 
CWR22 human prostate or WSU-DLCL2 (human diffuse large B-cell lymphoma 
[DLBCL]) tumors.  Pharmacodynamic responses in xenograft tumors were analyzed by 
assessing 20S proteasome inhibition and by evaluating levels of accumulated protein 
markers such as deoxyribonucleic acid (DNA) damage-inducible protein 34 (GADD34) 
and activating transcription factor-3 (ATF-3) as well as measuring growth arrest.  
Increased expression of GADD34 and ATF-3 is indicative of a downstream biological 
response to proteasome inhibition.  After a single dose of MLN2238, a clear dose 
response was observed in CWR22 xenografts as seen in both tumor 20S proteasome 


 
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inhibition and in changes in GADD34 and ATF-3 expression.  In WSU-DLCL2 
xenografts, greater tumor proteasome inhibition was observed with MLN2238 compared 
to bortezomib and resulted in increased expression of GADD34 and ATF-3. MLN2238 
efficacy experiments demonstrated strong antitumor activity in 4 xenograft models: 
CWR22 (a human prostate cancer cell line) and 3 human lymphoma cell lines (WSU-
DLCL2, OCI-Ly7-7D1-luc, and PHTX-22L).  In the case of the CWR22 xenograft 
model, significant antitumor activity was seen with both IV and PO dosing, 
demonstrating that this molecule has antitumor activity when administered via different 
dosing routes.  In all 3 lymphoma lines, MLN2238 demonstrated stronger antitumor 
activity than did bortezomib. In summary, MLN2238, similar to bortezomib, is a 
dipeptide boronic acid proteasome inhibitor that potently, reversibly, and selectively 
inhibits the proteasome.  There are several features, such as sustained pharmacodynamic 
effects and activity in a bortezomib-refractory lymphoma xenograft model, that suggest 
that it may have activity that extends beyond that seen with bortezomib. 
 
Nonclinical Pharmacokinetics and Pharmacodynamics: Nonclinical Pharmacokinetics: 
The pharmacokinetic (PK) properties of MLN2238 were studied in severe combined 
immunodeficient (SCID) mice bearing human CWR22 tumor xenografts, Sprague-
Dawley rats, beagle dogs, and cynomolgus monkeys.  Because of the extensive red blood 
cell (RBC) partitioning of MLN2238, both blood and plasma PK parameters were 
determined in these studies.  MLN2238 had a very low blood clearance (CLb) and a 
moderate blood volume of distribution at steady-state (Vss,b) after IV administration.  
The concentration-versus-time curve of MLN2238 displayed a distinct bi-exponential 
profile with a steep initial distribution phase and a long terminal t1/2 (> 24 hr) in all 
species tested.  MLN2238 had higher plasma clearance (CLp) and a larger plasma 
volume of distribution at steady-state (Vss,p) than in blood, largely because of the 
extensive RBC partitioning. The PK properties of MLN2238 after oral administration 
were studied in rats and dogs.  The plasma oral bioavailability (F) was 41% in rats and 
nearly 100% in dogs.  A clinical prototype formulation of the Ixazomib capsule 
demonstrated that MLN2238 had excellent oral F and an excellent absorption profile in 
dogs.  In addition, interindividual variability, as measured by %CV, in Cmax and AUC0-
24hr after oral administration was low to moderate, similar to that after IV administration.  
The terminal t1/2 after oral administration was also similar to that after IV administration.  
Comparison of the PK profiles after IV or PO administration in the dog is reported in 
further detail in the IB. MLN2238 is predicted to have very low CLb (0.0045 L/hr/kg) 
and a moderate Vss,b (0.79 L/kg) with a long terminal t1/2 (> 24 hours) in humans.  The 
human efficacious IV dose of MLN2238 is predicted to be 2.0 mg/m2 (0.054 mg/kg) 
twice weekly. The human efficacious oral dose is predicted to be between 2 and 5 mg/m2 
twice weekly, based on a predicted oral F of between 41% (as seen in rats) and 100% (as 
seen in dogs).  The efficacious dose projection for once weekly oral would be higher than 
twice weekly oral (data not provided). 
 
Metabolism appears to be a major route of elimination for MLN2238 and urinary 
excretion of the parent drug was negligible (< 5% of dose).  In vitro in liver microsomes, 
the metabolism of MLN2238 was high in mice and low to moderate in all other species 
studied.  MLN2238 is metabolized by multiple cytochrome P450 (CYP) isozymes and 
non-CYP enzymes and proteins.  The rank order of relative biotransformation activity of 
each of the 5 major human CYP isozymes in the in vivo studies was 3A4 (34.2%) > 1A2 
(30.7%) > 2D6 (14.7%) > 2C9 (12.1%) > 2C19 (negligible). 
 


 
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MLN2238 is neither an inhibitor of CYP isozymes 1A2, 2C9, 2C19, 2D6, or 3A4 (IC50 
> 30 μM, with an estimated inhibition dissociation constant [Ki] > 15 μM) nor a time 
dependent inhibitor of CYP3A4/5 (up to 30 μM).  The potential for Ixazomib treatment 
to produce DDIs via CYP inhibition is inferred to be low. 
 
In a Caco-2 cell assay, MLN2238 showed medium permeability with a B-to-A/A-to-B 
permeability ratio of 2.9.  MLN2238 may be a low-affinity substrate of para-glycoprotein 
(P-gp), breast cancer resistance protein (BCRP), and multidrug resistance protein 2 
(MRP2) efflux pump transporters.  MLN2238 is not an inhibitor of P-gp, BCRP, and 
MRP2 (IC50 > 100 μM).  Consequently, the potential for MLN2238 to cause DDIs with 
substrates or inhibitors of P-gp, BCRP, and MRP2 is low.   
 
See the IB for further details. 
 
1.4 
Safety Pharmacology: In exploratory safety pharmacology studies, MLN2238 was a 
weak inhibitor of the cloned cardiac potassium (K+) human ether à-go-g o related gene 
(hERG) channel, with an IC50 of 59.6 μM, which exceeds, by approximately 200-fold, 
the plasma Cmax (111 ng/mL [0.3 μM]) predicted to occur in humans at the optimally 
efficacious dose after IV administration. 
 
In the GLP-compliant, 1-cycle, repeat-dose, PO toxicology study in beagle dogs, an 
increase in QTc was seen in male dogs at non-tolerated doses, and a potential increase in 
QTc was seen in male dogs at tolerated doses.  However, increased QTc was not seen in 
female dogs at any dose, despite the fact that female dogs had plasma Cmax values 
similar to those of male dogs.  Additionally, in a GLP-compliant, 2-cycle, repeat-dose, IV 
toxicology study in beagle dogs, no increase in QTc was seen in either male or female 
dogs at any dose, even though dogs in the IV study had higher MLN2238 plasma Cmax 
values than did the male dogs in the PO study.  These data suggest that MLN2238 has a 
low potential for prolonging the QT interval in vivo. 
 
Toxicology: All studies discussed in this section were conducted with a solution of either 
MLN2238 or MLN2238 in equilibrium with Ixazomib.  Because Ixazomib was shown to 
dissociate immediately to MLN2238 upon exposure to plasma in vitro and therefore 
could not be detected in plasma samples in vitro all doses, concentrations, and PK 
parameters noted, here and in the IB, are expressed as the boronic acid, MLN2238. 
 
The toxicology studies of MLN2238 were studied in SCID mice bearing human CWR22 
tumor xenografts, Sprague-Dawley rats, beagle dogs, and cynomolgus monkeys.  Details 
of these studies are included in the IB. 
 
In Vitro Toxicology: MLN2238 was not mutagenic in a Good Laboratory Practice 
(GLP)-compliant bacterial reverse mutation assay (Ames assay).  
 
In Vivo Toxicology: Details of the in vivo toxicology IV dosing and oral dosing studies 
are provided in the IB.  To summarize, the toxicologic effects seen in the IV and PO 
studies are qualitatively similar to what was previously observed in rodents dosed with 
bortezomib, for which Ixazomib is the next-generation molecule.  MLN2238 did not 
cause significant toxicities that have not been previously observed after dosing with 
bortezomib.  Therefore, on the basis of the similarity in the toxicity profile in rats 
between MLN22338 and bortezomib, MLN2238 is not known to present any additional 
safety risks beyond those that occur after treatment with bortezomib.  In addition, there 


 
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were no significant findings at tolerated exposures in dogs observed after PO 
administration that were not seen after IV administration, and similar exposures were 
tolerated regardless of the route of administration. 
 
The potential risks identified from nonclinical studies in dogs and rats include: 
• 
GI toxicity that could result in nausea, vomiting, diarrhea, dehydration, 
electrolyte imbalance, bleeding, bowel obstruction including ileus and intussusception, 
and sepsis. 
• 
Reduced blood counts manifest as thrombocytopenia, neutropenia, and anemia.  
Reticulocytopenia was described in animals and may be associated with anemia.  
Reductions in blood counts may predispose to an increased susceptibility to infection, 
bleeding, and anemia. 
• 
Peripheral nerve ganglia effects that may be associated with peripheral 
neuropathy that includes pain, burning sensation, and numbness.  Autonomic and motor 
neuropathy may be observed, as both have been reported for bortezomib. 
• 
Lymphoid cell depletion that may be associated with increased risk of infection, 
including re-activation of herpes zoster. 
• 
Acute phase response that may result in fever and metabolic changes. 
 
All of the effects seen in the GLP-compliant PO toxicology studies in both dogs and rats 
at tolerated doses were reversible/reversing and can be monitored in the clinic with 
routine clinical observations (GI disturbances and infections secondary to lymphoid 
compromise), clinical pathology assessments (inhibition of erythropoiesis, 
thrombocytopenia, and inflammatory leukogram), and neurologic assessment, as are 
commonly done for patients treated with bortezomib.  The neurologic lesions in these 
studies are similar to what has been described after treatment with bortezomib and are 
believed to be the cause of the peripheral neuropathy observed in patients treated with 
bortezomib. 
 
Further details are presented in the IB. 
 
Clinical Experience with Ixazomib 
 
As of 30 April 2012, 382 patients have been treated with Ixazomib across 9 enrolling, 
sponsor-led phase 1 or phase 1/2 studies evaluating both twice-weekly and weekly dosing 
schedules.  Ixazomib is available as an intravenous and oral formulation. Regardless of 
the route of administration in the twice-weekly dosing schedule, Ixazomib is given on 
Days 1, 4, 8, and 11 of a 21-day cycle; in the weekly dosing schedule, the drug is given 
on Days 1, 8, and 15 of a 28-day cycle. To date, the development of oral Ixazomib has 
focused on multiple myeloma [relapsed and/or refractory and newly diagnosed] and a 
different yet related plasma cell dyscrasia, systemic light chain (AL) amyloidosis. A 
clinical pharmacology study looking at drug-drug interactions, the effect of food, and 
bioavailability also uses the oral formulation. Details of these trials can be found in 
ClinicalTrials.gov and the Ixazomib IB.     
 
 
 
 
Pharmacokinetics and Drug Metabolism: Clinical IV and PO pharmacokinetic (PK) data 
show that Ixazomib (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 is rapidly absorbed with a median time to first maximum 
plasma concentration (Tmax) of approximately 0.5 to 2.0 hours and terminal t1/2 after 


 
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multiple dosing of approximately 5 to 7 days.15  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.16  Based on these data, a recommendation 
was made for fixed dosing in clinical trials.  An absolute bioavailability of 67% was 
determined for Ixazomib using the population PK analysis.  See the IB for information on 
the PK for IV doses of Ixazomib. 
 
Metabolism appears to be the major route of elimination for Ixazomib, with negligible 
urinary excretion of the parent drug (< 3% of dose).  In vitro studies of liver microsomes 
show that Ixazomib is metabolized by multiple cytochrome P450 enzymes (CYPs) and 
non-CYP enzymes/proteins.  The rank order of relative biotransformation activity of the 
5 major human CYP isozymes is 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 is it a time-dependent inhibitor of CYP3A4/5.  The potential for Ixazomib 
treatment to produce DDIs via CYP inhibition is inferred to be low; however, there may 
be a potential for DDIs with a concomitant strong CYP3A4 or CYP1A2 inhibitor 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 (P-gp), breast cancer resistance protein (BCRP), and multidrug 
resistance associated protein (MRP2) efflux pump transporters.  Ixazomib is not an 
inhibitor of P-gp, BCRP, and MRP2.  The potential for DDIs with substrates or inhibitors 
of P-gp, BCRP, and MRP2 is, therefore, inferred to be low. 
      
 
 
Clinical Trial Experience Using the Oral Formulation of Ixazomib:  
In the 7 studies actively enrolling patients to investigate oral Ixazomib in patients with 
differing malignancies (multiple myeloma, AL amyloidosis, nonhematologic cancers, and 
lymphoma), a total of 242 patients have been treated as of 30 April 2012. These patients 
have been treated with different doses of Ixazomib, either as a single agent treatment or 
in combination with currently clinically available treatments. Information regarding the 
ongoing studies, patient populations, and doses investigated are included in Table 1-1. 


 
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Table 1-1   
Ongoing Studies of Oral IXAZOMIB 
Trial/ 
Population 
Description 
Doses Investigated 
C16003 
RRMM 
N = 58 
PO, twice weekly (TW), 
single agent 
0.24-2.23 
mg/m2
, TW 
MTD:  2.0 mg/m2 
DLT:  rash, thrombocytopenia 
C16004 
RRMM 
N = 52 
PO, weekly (W), single 
agent 
0.24-3.95 
mg/m2
, W 
MTD:  2.97 mg/m2 
DLT:  rash, nausea, vomiting, 
diarrhea 
C16005 
NDMM 
N = 65 
PO, W, combination with 
LenDex 
28 day cycle 
1.68-3.95 
mg/m2
, W 
MTD:  2.97 mg/m2 
DLT:  nausea, vomiting, 
diarrhea, syncope 
RP2D*:  4.0 mg fixed 
(switched to fixed dosing in 
phase 2, relevant to 2.23 
mg/m2) 
C16006 
NDMM 
N = 28 
PO, TW (Arm A- 42 day 
cycle) and W 
(Arm B- 28 day 
cycle), 
combination 
with melphalan 
and prednisone 
Arm A*:  3-3.7 
mg, 
fixed 
dose, 
TW 
DLT: rash, thrombocytopenia, 
subileus 
Arm B*:  5.5 mg, fixed dose, 
W 
DLT: Esophageal ulcer 
C16007 
RR-AL 
N = 6 
PO, W, single agent 
4-5.5 mg, fixed 
dose*, 
W 
MTD: 4 mg 
DLT: thrombocytopenia, 
dirrhea, dyspnea, acute rise in 
creatinine, cardiac arrest 
 
C16008 
NDMM 
PO, TW, combination 
with LenDex 21 
day cycle 
3.0-3.7 mg 
fixed 
dose* 


 
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Table 1-1   
Ongoing Studies of Oral IXAZOMIB 
N=11 
W 
MTD: 4 mg 
DLT: 
C16009 
Solid tumors, Lymphomas 
N = 22 
PO, W, single agent 
5.5 mg fixed 
dose* 
W 
C16010 
RRMM 
N = 1 
PO, W, combination with 
LenDex 
4.0 mg fixed 
dose* 
W 
TB-
MC
010
034 
RRMM 
N = 5 
PO, W, single agent in 1s 
part of study 
then in 
combination 
with LenDex in 
2nd part 
3.0 mg fixed 
dose* 
W 
DLT: thrombocytopenia, 
nausea, hypertension, diarrhea 
Abbreviations:  RRAL = Relapsed or refractory Primary systemic light chain (AL) amyloidosis; BSA = 
body surface area ; DLT = dose-limiting toxicity; IV = intravenuously; LenDex = lenalidomide plus 
dexamethasone; MTD = maximum tolerated dose; NDMM = newly diagnosed multiple myeloma; PO 
= orally; RRMM = relapsed and/or refractory multiple myeloma; RPh2D = recommended phase 2 dose 
* Approximate body surface area (BSA) and fixed dosing equivalence:  3 mg ~ equivalent to 1.68 mg/m2 
BSA dosing; 4.0 mg ~ equivalent to 2.23 mg/m2 BSA dosing; and 5.5 mg ~ equivalent to 2.97 mg/m2 
BSA dosing. 
 
Overview of the Oral Formulation of Ixazomib 
The emerging safety profile indicates that oral Ixazomib is generally well tolerated with 
predominant toxicities largely reversible, able to be monitored by routine clinical 
examinations and manageable by dose reductions, discontinuation, or standard supportive 
care. From experience from phase 1 through 2 studies the major toxicities can be 
managed to allow repeat treatment cycles over periods extending beyond 24 months.  
In the 4 ongoing studies (C16003, C16004, C16007, and C16009) investigating single-
agent oral Ixazomib in patients with differing malignancies (multiple myeloma, AL 
amyloidosis, nonhematologic cancers, and lymphoma), a total of 146 patients have been 
treated as of 30 April 2012. These patients have been treated with different doses of 
Ixazomib as they are all phase 1 trials. An overview of the most frequent (at least 10%) 
AEs occurring in the pooled safety  population from single-agent oral Ixazomib Studies 
(C16003, C16004, C16007, and C16009) is shown in Table 1-2. 
Table 1-2 
Summary of Most Common (At Least 10% of Total) All Grade Treatment-
Emergent Adverse Events (Oral Ixazomib Single-Agent [C16003/4/7/9] Safety 
Population) 
Primary System Organ Class  
Preferred Term and Incidence 
N=146 
n (%) 


 
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Subjects with at Least One Adverse Event 135 
(92) 
 
Gastrointestinal disorders 102 (70) 
Nausea 68 (47); Diarrhoea 55 (38); Vomiting 51 
(35); Abdominal pain 21 (14); Constipation 21 (14) 
General disorders and 
administration site 
conditions 98 (67) 
Fatigue 71 (49); Pyrexia 31 (21); Oedema 
peripheral 15 (10) 
Blood and lymphatic system 
disorders 77 (53) 
Thrombocytopenia 60 (41); Anaemia 30 (21); 
Neutropenia 23 (16); Leukopenia 15 (10) 
Nervous system disorders 63 (43) 
Headache 20 (14); Dizziness 18 (12) 
Metabolism and nutrition 
disorders 60 (41) 
Decreased appetite 39 (27) Dehydration 21 (14) 
Respiratory, thoracic and 
mediastinal disorders 60 
(41) 
Cough 22 (15); Dyspnoea 21 (14) 
Skin and subcutaneous tissue 
disorders 60 (41) 
Rash macular 17 (12) 
Musculoskeletal and connective 
tissue disorders 56 (38) 
Arthralgia 20 (14); Back pain 17 (12) 
Infections and infestations 54 (37) 
Upper respiratory tract infection 21 (14) 
Source: Ixazomib Investigator’s Brochure Edition 6 
 
Treatment emergent is defined as any AE that occurs after administration of the first dose 
of any study drug through 30 days after the last dose of any study drug, any event that is 
considered drug-related regardless of the start date of the event, or any event that is 
present at baseline but worsens in intensity or is subsequently considered by the 
investigator to be drug-related.  
 
Subject Incidence: A subject counts once for each preferred term. Percentages use the 
number of treated subjects as the denominator 
 
In the 3 studies actively enrolling patients to investigate oral Ixazomib in combination 
with standard combination regimens in patients with newly diagnosed multiple myeloma, 
a total of 96 patients have been treated as of 30 April 2012. These patients have been 
treated with different doses of Ixazomib in combination with lenalidomide and 
dexamethasone in 2 trials (C16005 and C16008) and with melphalan and prednisone in 1 
trial (C16006). The most frequent (at least 10%) adverse events occurring in the pooled 
safety population from Studies C16005, C16006, and C16008 is shown in Table 1-3. In 
combinations trials, related is defined as possibly related to any drug in the combination 
regimen, not just specifically related to Ixazomib. 
 
Table 1-3 
Summary of Most Common (At Least 10% of Total) Treatment- Emergent Adverse 
Events (Oral Ixazomib Combination Agent [C16005/6/8] Safety Population) 
 
Primary System Organ Class  
Preferred Term and Incidence 
N= 96 
n (%) 
Subjects with at Least One Adverse Event 135 
(92) 
 
 


 
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Gastrointestinal disorders 70 (73) 
Nausea 32 (33); Constipation 29 
(30); Vomiting 25 (26) 
Diarrhoea 22 (23) 
General disorders and 
administration site 
conditions 64 (67) 
Fatigue 37 (39); Oedema peripheral 
20 (21); Pyrexia 19 (20) 
Skin and subcutaneous tissue 
disorders 57 (59) 
Rash 13 (14) 
Nervous system disorders 46 (48) 
Neuropathy peripheral 13 (14); 
Dysgeusia 12 (13) 
Dizziness 11 (11) 
Musculoskeletal and connective 
tissue disorders 45 (47) 
Back pain 18 (19); Muscle spasms 10 
(10) 
Blood and lymphatic system 
disorders 42 (44) 
Thrombocytopenia 28 (29); Anaemia 
22 (23);  
Neutropenia 19 (20) 
Infections and infestations 40 (42) 
Upper respiratory tract infection 17 
(18);  
Metabolism and nutrition disorders 
38 (40) 
Decreased appetite 11 (11) 
Respiratory, thoracic and 
mediastinal disorders 34 
(35) 
Dyspnoea 13 (14); Cough 11 (11) 
Psychiatric disorders 23 (24) 
Insomnia 15 (16) 
Source: Ixazomib Investigator’s Brochure Edition 6. 
 
Treatment emergent is defined as any AE that occurs after administration of the first dose 
of any study drug through 30 days after the last dose of any study drug, any event that is 
considered drug-related regardless of the start date of the event, or any event that is 
present at baseline but worsens in intensity or is subsequently considered by the 
investigator to be drug-related. 
Subject Incidence: A subject counts once for each preferred term. Percentages use the 
number of treated subjects as the denominator. 
 
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 (advanced solid tumors [3], non-Hodgkin’s disease, Hodgkin’s 
disease [4], relapsed and/or refractory multiple myeloma [RRMM; 5; 6], relapsed or 
refractory systemic light chain amyloidosis [RRAL; 7], and newly diagnosed multiple 
myeloma [NDMM; 8; 9; 10]) to date. 
 
Though additional data are needed to characterize the clinical benefit of this drug, the 
emerging data supports the ongoing development of Ixazomib. 
 
Of particular relevance to this study (C16011) is the clinical experience from Studies 
C16004 and C16007 in which single-agent Ixazomib is administered weekly in patients 
with RRMM or RRAL, respectively.  


 
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Relapsed MM: Single-agent, Weekly Ixazomib (Study C16004):  
Study C16004 is an open-label, dose-escalation, phase 1 study of Ixazomib administered 
weekly on Days 1, 8, and 15 of a 28-day cycle in adult patients with RRMM. Patients 
with MM enrolled in the dose-escalation component of the study have relapsed following 
at least 2 lines  of therapy, which must have included bortezomib, thalidomide (or 
lenalidomide), and corticosteroids. The dose-escalation phase of the trial has completed. 
In this study, 2 of 3 patients experienced protocol-defined DLTs (Grade 3 rash and Grade 
3 nausea, vomiting, and diarrhea) at a dose of 3.95 mg/m2. As per protocol, subsequent 
patients were treated at 1 dose level below (2.97mg/m2) where 1 of 6 patients 
experienced a DLT (Grade 3 nausea, vomiting, and diarrhea). The MTD of weekly oral 
Ixazomib was determined to be 2.97 mg/m2. 
 
Once the MTD was established, cohorts of patients representing the heterogeneous 
patient population currently seen in clinical practice were enrolled in order to further 
evaluate the safety, tolerability, efficacy, PK, and pharmacodynamics of oral Ixazomib. 
The MTD expansion cohorts enrolling are: 
 
1. Relapsed and Refractory expansion cohort [refractory is defined as disease progression 
while on therapy or within 60 days after the last dose of therapy]; 
2. Carfilzomib expansion cohort 
3. Proteasome Inhibitor-Naïve expansion cohort 
4. VELCADE-Relapsed expansion cohort 
Final study results are not available for this ongoing trial, but preliminary data suggest 
Ixazomib has antitumor activity in heavily pretreated MM patients, with durable 
responses/disease control, and is generally well tolerated.[11,12] 
 
As of the 30 April 2012 data cut, these patients are considered heavily pretreated as 
evidenced by a median number of 4 (range 1–13) prior lines of therapy, with 66% 
refractory to the last line of therapy. Patients have received a median of 2 cycles of 
therapy (range, 1- 11). Five patients have achieved objective response: 1 patient achieved 
a VGPR and 4 patients achieved a PR. Additionally, 15 patients achieved durable disease 
stabilization for up to 9.5 months. At data cut-off, 15 patients remain on treatment; 
discontinuation of treatment was primarily due to progressive disease (69%). 
 
A summary of the safety profile of patients treated in Study C16004 is outlined in Table 
1-4. 
Overall, 92% of patients experienced a TEAE of any grade and of any cause. Peripheral 
neuropathy was limited to Grade 1/ 2 in 6 patients, with 3 patients reporting baseline 
Grade 1 PN at study entry. 
 
Table 1-4    
Study C16004, Oral Ixazomib, Single Agent, Given Weekly:  Most Common 
TEAEs as of 30 April 12 (N= 52) 
Most Common (> 20%) Any Grade and 
Irrespective of Cause 
Thrombocytopenia (54%) 
Fatigue (48%) 
Nausea (44%), diarrhea (44%) 


 
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Vomiting (37%) 
Decreased appetite (33%) 
Rash* (31%) 
Anemia (25%) 
Neutropenia (23%) 
Drug-Related Grade ≥ 3 in > 5% of patients 
 
Thrombocytopenia (38%) 
Diarrhea and neutropenia 17% (each), fatigue 
and lymphopenia 10% (each), nausea and 
decreased appetite 8% (each) and vomiting 6% 
 
Source: Ixazomib Investigator’s Brochure Edition 6 
* Rash includes preferred terms of rash macular, rash, maculo-papular, rash morbilliform, rash 
pruritic, 
pruritus,, rash erythematous, exfoliative rash, and rash popular 
 
Dose reductions required were due to AEs that included rash, neutropenia, 
thrombocytopenia, diarrhea, nausea, vomiting, dehydration, hypotension, increase in 
serum creatinine, abdominal pain, ileus, fatigue, and pneumonia. The AEs reported for 
the 5 patients who were required to discontinue treatment included Grade 2 Ixazomib-
related nausea/vomiting in 1 patient treated above the MTD, Grade 3 Ixazomib-related 
diarrhea in a second patient, related Grade 3 thrombocytopenia, related Grade 2 dyspnea, 
and notrelated Grade 4 elevation in creatinine(1 patient each). There were no on-study 
deaths.  
Newly Diagnosed Multiple Myeloma (C16005):  
In Study C16005, Ixazomib is given weekly (Days 1, 8, and 15), in combination with 
lenalidomide (Days 1-21), and dexamethasone (Days 1, 8, 15, and 22) in a 28-day cycle.  
Enrollment to this study is closed.   
 
Clinical data as of 30 April 2012 is available.  The MTD in Study C16005 was 
determined to be 2.97 mg/m2 given weekly in a 28-day cycle with LenDex.  The DLTs 
were urticarial rash, dizziness, nausea, orthostatic hypotension, vomiting, diarrhoea, and 
syncope.  The recommended phase 2 dose (RP2D) estimation was established following 
evaluation of the available data from the phase 1 portion of the trial which included, but 
was not limited to, analyses of efficacy results and adverse events (Grade 3/4 AEs, SAEs, 
all grades peripheral neuropathy, and treatment discontinuation).  Given that the dose of 
Ixazomib at 2.97 mg/m2 compromised the maximal dosing of lenalidomide and that the 
dose of 2.23 mg/m2 is very tolerable and clinically active, Millennium designated 2.23 
mg/m2 as the RP2D after evaluation of the data and discussion with investigators.  The 
RP2D of 2.23 mg/m2 has been translated into a fixed dose of 4.0 mg based on the results 
from the population PK analysis.  Enrollment in this study has been completed; final 
study results are not available, but preliminary data suggests oral Ixazomib given weekly 
plus lenalidomide and dexamethasone in a 28-day cycle appears well tolerated with 
manageable toxicity and encouraging antitumor activity.   
 
In Study C16005, 15 of 15 (100%) patients in the dose escalation portion of the study 
experienced at least 1 TEAE irrespective of grade or causality.  At the MTD across all 
dose expansion cohorts 49 of 53 patients (including 3 patients from the dose escalation 


 
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cohort [92%]) reported at least 1 TEAE irrespective of grade or causality.  In the MTD 
cohorts, fatigue was the most common AE reported (38%).  Other common AEs reported 
include nausea (32%), constipation (30%), upper respiratory infection (23%), and 
peripheral oedema (21%).  Skin toxicity, primarily erythematous rash, occurred in 62% 
of patients (of note, rash is an overlapping toxicity with Ixazomib and lenalidomide).  
Peripheral neuropathy was reported in 13% of patients; Grade 3 in 1 patient.   
 
A summary of the overall safety profile of patients treated in Study C16005 is outlined in 
Table 1-6.  Overall, 100% of 65 patients experienced at least one TEAE of any grade and 
of any cause.   
 
Table 1-5    
Study C16007, Oral Ixazomib, Single Agent Given Weekly  Most 
Common TEAEs as of 30April 12 (N = 14) 
Most Common (> 20%) 
Any Grade and Irrespective of Cause 
Nausea (50%) 
Fatigue (36%) 
Thrombocytopenia (29%) 
Diarrhea (29%) 
Decreased Appetite (21%) 
Peripheral Edema (21%) 
Dyspnea (21%) 
Abdominal pain (21%) 
Drug-Related Grade ≥ 3 in more than 3 Patients  
Thrombocytopenia 5 patients, rash 3 patients, 
dehydration 2 patients, fatigue 2 patients 
 
Source: Ixazomib Investigator’s Brochure Edition 6 
 
One patient discontinued study drug administration due to a TEAE (patient with DLT of 
acute rise in serum creatinine, dyspnea, and cardiac arrest treated at 5.5 mg, as noted 
above). No death has been reported. 
The potential risks reported with Ixazomib use, pooled from all studies using the oral 
formulations, were anticipated based on preclinical data and previous experience with 
VELCADE and are noted in the Ixazomib IB, SMA, and ICF documents. Regardless of 
whether Ixazomib is administered on the once weekly or twice weekly dosing schedule, 
there is consistency among the type of TEAEs reported, despite some differences in the 
frequency and severity of the reported events. While the predominant potential toxicities 
may be severe in some cases, they are largely reversible, and can be managed by routine 
clinical monitoring and standard medical interventions, which may include dose 
reductions and supportive care. Please refer to the Ixazomib IB and SMA for further 
information. 
Table 1-6    
Study C16005:  Oral Ixazomib Given Weekly in Combination With 
Lenalidomide and Dexamethasone, Most Common TEAEs as of 30 April 
2012 
Most Common (> 20%) Any Grade and 
Fatigue (37%) 


 
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Irrespective of Cause 
Nausea (34%) 
Constipation (31%) 
Vomiting (28%) 
Diarrhoea (26%) 
Thrombocytopenia (23%) 
Upper respiratory tract infection (22%) 
Anaemia and oedema peripheral ( 20% each) 
Drug-Relateda Grade ≥ 3 in ≥ 2 Patients  
Nausea, vomiting (n=3 each)  
Thrombocytopenia, lymphopenia, rash pruritic 
(n=2 each ) 
 
Source: Ixazomib Investigator’s Brochure Edition 6. 
a 
Related means to ANY drug in the study drug combination. 
 
The most common drug-related SAEs reported in Study C16005 as of 30 April 2012 
include pneumonia, infection, diverticulitis, localised infection, gastrointestinal 
haemorrhage, respiratory syncytial virus (RSV) pneumonia faecaloma, pyrexia, 
pneumonia respiratory syncytial viral, non-cardiac chest pain, peripheral oedma, asthenia, 
hyponatraemia vomiting, diarrhoea, nausea, chest pain, dehydration, anemia, dizziness, 
peripheral sensory neuropathy, orthostatic hypotension, embolism, muscular weakness, 
acute renal failure, blood creatinine increased, maculopapular rash, atrial fibrillation, 
syncope, hypotension, and deep vein thrombosis, and back pain.   
 
As of the clinical data cutoff, 4 patients have discontinued treatment due to TEAEs 
including gastrointestinal haemorrhage, angioedema, syncope, and RSV pneumonia. 
 
One death was reported for a patient with RSV pneumonia; the event was deemed by the 
investigator to be related to treatment with Ixazomib.   
 
1.6  
Anti-myeloma activity of Ixazomib:  
 
Several clinical trials have been conducted with Ixazomib in patients with relapsed 
myeloma as well as newly diagnosed myeloma. These have included trials of Ixazomib as 
a single agent, in combination with dexamethasone, as well as in combination with 
lenalidomide. As mentined before, two different dose schedules have been explored as 
well; once weekly for 3 out of four weeks and twice weekly for 2 out of 3 weeks.  
 
Ixazomib was studied as a single agent in patients with relapsed and or refractory MM 
(NCT00932698).17 The trial was designed to assess safety, MTD, and response rate with 
twice-weekly oral Ixazomib. Patients with ≥2 prior therapies (including bortezomib, 
thalidomide/lenalidomide, and corticosteroids) were enrolled and treated with Ixazomib 
on d 1, 4, 8, and 11 of 21-d cycles. At the MTD (2.0 mg/m2), patients were enrolled to 
relapsed and refractory [RR], bortezomib-relapsed [VR], proteasome-inhibitor [PI] naïve, 
and carfilzomib [CZ] expansion cohorts. Fifty-eight patients were enrolled, 38 to the 
expansion cohorts (19 RR, 11 VR, 6 PI naïve, 2 CZ). Patients have received a median of 
3 cycles (range 1-24) to date (data cut-off Dec 1, 2011); 7 (12%) have received ≥13 
cycles. Of 53 response-evaluable patients, 6 have achieved ≥PR, with 1 sCR (PI naïve 
cohort) and 5 PRs (2 in dose-escalation, 1 in RR, 2 in VR cohorts), and 1 VR patient has 
achieved MR, with duration of disease control of up to 18.6 months (Figure 1 below). 


 
23  
MC1382 
Millennium # X16009 
 
 
                     MCCC Add 13 
Protocol Version Date:    February 23, 2021 
 
 
 
 
In a very similar trial Ixazomib was administered once weekly for 3 weeks in 4 week 
cycles. (NCT00963820).18 Patients with relapsed/refractory MM who had ≥2 prior 
therapies (including bortezomib, thalidomide/lenalidomide, and corticosteroids) were 
treated with Ixazomib on d 1, 8, and 15 of 28-d cycles. At the MTD, patients were to be 
enrolled to relapsed and refractory (RR), bortezomib-relapsed (VR), proteasome inhibitor 
(PI) naïve, and carfilzomib (CZ) expansion cohorts. Overall, 52 patients have been 
enrolled, 32 in the dose-escalation phase (0.24–3.95 mg/m2) and 23 to expansion cohorts 
(12 RR, 5 VR, 5 PI naïve, 1 CZ). Patients have received a median of 2 cycles (range 1–
11); 15 patients remain on treatment at last follow up. In 18 response-evaluable patients, 
1 had a VGPR at 3.95 mg/m2, 1 had a PR at 2.97 mg/m2, 2 had a PR in the expansion 
cohorts and 12 have achieved SD durable for up to 9.5 months (Figure 2 below).  
 
 
 
Cycles 
Bortezomib-
relapsed 
cohort 
Relapsed/ 
refractory 
cohort 
PI-naïve 
cohort 
2.23 mg/m2 
2.0 mg/m2 
1.68 mg/m2 
1.2 mg/m2 
0.8 mg/m2 
0.48 mg/m2 
0.24 mg/m2 
MR, cycle 4, PR cycle 6, 
VGPR, cycle 10 
MR, cycle 2 
PR, cycle 2 
MR, cycle 4, PR, cycle 6 
MR, cycle 2 
VGPR, cycle 2, sCR, end of treatment 
PR, cycle 6 
PR, cycle 4, near-CR, cycle 26 
* 
* 
* 
* 
* 
* 
* 
*Ongoing on treatment 
* 




 
25  
MC1382 
Millennium # X16009 
 
 
                     MCCC Add 13 
Protocol Version Date:    February 23, 2021 
 
Ixazomib 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 [3,4,5,6,8,9,10]. 
This study will be conducted in compliance with the protocol, good clinical practice 
(GCP), applicable regulatory requirements, and International Conference on 
Harmonisation (ICH) guidelines 
 
1.8 
Role of maintenance therapy in myeloma: The concept of maintenance therapy has 
been tested mostly in the setting of high dose therapy and autologous stem cell 
transplantation. Patients invariably relapse after initial treatment strategies including SCT 
and various trials have attempted to maintain the SCT response through maintenance 
approaches. Initial trials prior to the availability of the new drugs have examined steroids 
or interferon, and a small randomized clinical trial of interferon- (3 x 106 units/m2) 
subcutaneously 3 times weekly, following initial ASCT, suggested a modest 
improvement in EFS.20 The IFM99-02 trial randomized patients with standard-risk MM 
(Beta2-microglobulin [B2M] <3, no deletion 13), were: to receive no maintenance, 
pamidronate, or pamidronate plus thalidomide after tandem SCT.21 Thalidomide was 
associated with higher response rates, improved EFS (52% vs. 36% with no maintenance) 
and improved overall survival (4-year estimated survival from diagnosis with thalidomide 
(87%) compared with no maintenance (77%). At least 5 different randomized trials have 
examined the role of thalidomide as a maintenance therapy post-SCT.22-24 A meta-
analysis of these trials support the improved progression-free survival, but remains 
equivocal in terms of overall survival improvement. In addition, high discontinuation rate 
has been noted in all these studies due to toxicity. In particular the Canadian study 
showed worsening of QoL parameters among patients getting thalidomide maintenance.24  
 
A phase 3 study from the IFM enrolled 614 patients < 65 years, with non-progressive 
disease, within 6 months after upfront ASCT.25 Patients received 2 cycles of 
consolidation with lenalidomide 25 mg daily for 3 of 4 weeks followed by a 
randomization to lenalidomide 10-15 mg/d until relapse or to placebo (n=307 in each 
arm). Patients were stratified according to Beta-2M, del13, and VGPR to initial therapy. 
There was an improvement in the PFS with maintenance therapy, with a median PFS of 
42 months for lenalidomide vs. 24 months for the placebo. The improvement in the PFS 
was seen in all the subgroups based on stratification. With the current follow up, overall 
survival (OS) remains identical in the two groups. In a very similar trial, McCarthy and 
colleagues randomized patients 70 years or younger, who attained a stable disease or 
better with their induction therapy and underwent ASCT within one year of diagnosis, to 
lenalidomide (5-15 mg/day) or placebo until relapse.26 Patients were stratified based on 
Beta-2M and use of thalidomide or lenalidomide therapy during induction. Patients were 
enrolled prior to the ASCT, with 19% of the 568 enrolled dropping out before 
randomization. As expected, grade 3 and 4 adverse events were significantly higher in the 
maintenance arm, with hematological toxicities being the common events. The median 
time to progression was 42 months with lenalidomide compared to 21.8 months with the 
placebo, results very similar to the French study. More recent updates suggest an 
improvement in the overall survival for the lenalidomide arm in the CALGB study. There 
are differences, however, between the two trials in terms of the design as well as duration 
of therapy. Patients in the IFM trial received uniform induction therapy unlike the 
CALGB trial. Patients in the IFM study received 2 cycles of consolidation with 
lenalidomide before starting maintenance. In addition, the IFM trial limited maintenance 
to approximately 24 months based on concerns regarding second malignancies and did 


 
26  
MC1382 
Millennium # X16009 
 
 
                     MCCC Add 13 
Protocol Version Date:    February 23, 2021 
 
not allow cross over. However, the CALGB trial allowed cross over from placebo arm to 
lenalidomide maintenance based on interim analysis and also allowed maintenance until 
progression. 
 
Very few trials have explored the role of maintenance therapy outside of the context of 
SCT prior to the advent of the new drugs. Three large recent trials have explored the role 
of maintenance therapy in the older patient population following a defined period of 
initial therapy with 3 or 4 drug combinations. In a recent multicenter phase 3 study (MM-
015), Palumbo et al have evaluated the safety and efficacy of continuous lenalidomide 
treatment after MPR (MPR-R; n=152) versus MP (n=154) or MPR (n=153) in 459 newly 
diagnosed transplant ineligible MM patients who were >= 65 years of age.27 The 
treatment schema consisted of melphalan 0.18 mg/kg on days 1-4, prednisone 2 mg/kg on 
days 1-4, with (MPR or MPR-R) or without (MP) lenalidomide 10 mg/day on days 1-21 
for nine 28-day cycles. Following 9 cycles of MPR, patients received maintenance 
lenalidomide (10 mg/day on days 1-21) (MPR-R) or placebo (MPR) until progression; 
MP patients also received placebo until progression. After a median follow-up of 21 
months, MPR-R compared with MP resulted in a higher overall RR (77% vs. 50%, p < 
.001) and higher rates of CR (16% vs. 4%, p < .001). In addition, MPR-R reduced the risk 
of disease progression by 58% compared with MP (HR =0.423, p < .001) and resulted in a 
higher 2-year PFS rate (55% vs. 16%). Adverse events associated with MPR-R and MP 
resulted in treatment discontinuation in 20% and 8% patients, respectively. In another 
trial, patients receiving initial therapy with bortezomib, thalidomide, melphalan and 
prednisone were continued on maintenance with bortezomib and thalidomide, resulting in 
superior PFS compared to the control group of patients receiving VMP.28 Finally, a 
Spanish trial randomized patients to initial therapy with VMP or VTP and then 
randomized all patients at the end of therapy to maintenance with VT or VP and showed 
an improved PFS in patients getting VT maintenance. In all these trials patients assigned 
to receive maintenance therapy with an IMiD or bortezomib + IMiD combination 
appeared to have improvements in the depth of response and better progression-free 
survival.29  
 
However, significant questions remain as to the duration of maintenance therapy with 
different trials sporting different designs in terms of duration of therapy. Given the data 
showing that the rate of second malignancies may be higher after 24 months of 
maintenance, and the cost and side effects of maintenance, it has been suggested that two 
years of lenalidomide maintenance is sufficient, and the current IFM/DFCI trial has been 
amended to limit maintenance duration to two years.25 But the major improvement in OS 
seen with lenalidomide maintenance was with therapy until progression. Hence, the issue 
of optimal duration of maintenance is pressing.  
 
1.9   
Rationale for the current trial: Ixazomib is a second-generation proteasome inhibitor, 
with excellent oral bioavailability, that is currently in phase 1 and 2 clinical trials.30 The 
preliminary data from the phase 1 trials and the expansion cohorts at MTD, using single 
agent MLN 9708, demonstrates excellent tolerability and early evidence of efficacy.31,32 
In combination with lenalidomide in the setting of newly diagnosed myeloma, the 
combination has shown very high response rates and deep responses. Given these results, 
it is only logical to evaluate the efficacy of cyclophosphamide and Ixazomib with 
dexamethasone in the context of newly diagnosed disease. The results of this phase 2 can 
be compared with the historical controls form similar studies that have looked at Rd, 
VRd, and VCd, to give us an estimate of the comparative efficacy. We hypothesize that 
this fully oral regimen will have significant activity in this setting and will provide for a 


 
27  
MC1382 
Millennium # X16009 
 
 
                     MCCC Add 13 
Protocol Version Date:    February 23, 2021 
 
convenient schedule. In addition, given the clinical efficacy seen with bortezomib, 
cyclophosphamide and dexamethasone, we hypothesize that the combination of 
Ixazomib, cyclophosphamide and dexamethasone, will be active in light chain 
amyloidosis. 
 
2.0 
Goals    
 
 
2.1 
Primary 
 
2.11 
Phase 1 Cohort A: To determine the maximum tolerated dose of 
cyclophosphamide that can be combined with Ixazomib and dexamethasone in 
patient with previously untreated symptomatic MM. 
 
2.12 
Phase 2 Cohort A: To determine the complete plus very good partial response 
rate (>=VGPR) of Ixazomib, used in combination with cyclophosphamide and 
dexamethasone in patients with previously untreated symptomatic MM. 
 
2.13 
Phase 2 Cohort B:  To determine the hematologic response rate of Ixazomib, 
used in combination with cyclophosphamide and dexamethasone in patients with 
previously untreated light chain amyloidosis 
 
2.2 
Secondary 
 
2.21 
Cohort A: To determine the progression free survival and overall survival among 
patients with previously untreated symptomatic MM following treatment with 
Ixazomib in combination with cyclophosphamide and dexamethasone followed 
by Ixazomib maintenance till progression. 
 
2.22 
Cohort A: To determine the toxicities associated with Ixazomib in combination 
with cyclophosphamide and dexamethasone in patients with previously untreated 
symptomatic MM. 
 
2.23 
Cohort B:  To determine the organ response rate of Ixazomib, used in 
combination with cyclophosphamide and dexamethasone in patients with 
previously untreated light chain amyloidosis 
 
2.24 
Cohort B:  To determine the progression free survival and overall survival among 
patients with previously untreated light chain amyloidosis following treatment 
with Ixazomib in combination with cyclophosphamide and dexamethasone 
followed by Ixazomib maintenance till progression. 
 
2.25 
Cohort B:  To determine the toxicities associated with Ixazomib in combination 
with cyclophosphamide and dexamethasone in patients with previously untreated 
light chain amyloidosis. 
 
2.3 
Correlative Research 
 
2.31 
Cohort A: To examine the pharmacokinetics of Ixazomib when used in 
combination with cyclophosphamide and dexamethasone. 
 
2.32 
Cohort A: To assess the incidence of neurotoxicity using patient completed 
questionnaires. 
 
 


 
28  
MC1382 
Millennium # X16009 
 
 
                     MCCC Add 13 
Protocol Version Date:    February 23, 2021 
 
 
3.0 
Patient Eligibility 
 
Phase I only: Prior to discussing protocol entry with the patient, call the MCCC 
Registration Office 
for dose level and to insure that a place on the protocol is 
open to the patient.  
 
3.1 
Inclusion Criteria  
 
3.11 
Cohort A:  Multiple myeloma or  
Cohort B:  Biopsy proven light chain amyloidosis with organ involvement  
requiring therapy 
3.12 
Age ≥18 years. 
3.13 
The following laboratory values obtained ≤14 days prior to registration.  
• 
Calculated creatinine clearance (using Cockcroft-Gault equation below)* 
>=30 mL/min 
• 
Absolute neutrophil count (ANC) ≥1000/mm3 
• 
Platelet count ≥75000/mm3 
• 
Hemoglobin ≥8.0 g/dL 
• 
Total bilirubin ≤ 1.5 x ULN 
• 
ALT and AST ≤ 3 x ULN 
 
Cohort B only: 
• 
Alkaline phosphatase ≤750 U/L  
• 
NT-ProBNP < 7500 ng/dL  
*Cockcroft-Gault Equation: 
Creatinine clearance for males = (140 - age)(actual body weight in kg)  
(72)(serum creatinine in mg/dL) 
Creatinine clearance for females = (140 - age)(actual body weight in kg)(0.85) 
(72)(serum creatinine in mg/dL) 
 
 
3.14 
Prior therapy for the treatment of solitary plasmacytoma is permitted, but >14 
days should have elapsed from the last day of radiation. NOTE: Prior therapy 
with clarithromycin, DHEA, anakinra, pamidronate or zoledronic acid is 
permitted. Any additional agents not listed must be approved by the Principal 
Investigator. 
3.15 
Measurable disease of multiple myeloma as defined by at least ONE of the 
following: 
• 
Serum monoclonal protein ≥1.0 g/dL (see Section 11.1 for definition) 
• 
>200 mg of monoclonal protein in the urine on 24 hour electrophoresis  
• 
Serum immunoglobulin free light chain ≥10 mg/dL AND abnormal serum 
immunoglobulin kappa to lambda free light chain ratio. 
 


 
29  
MC1382 
Millennium # X16009 
 
 
                     MCCC Add 13 
Protocol Version Date:    February 23, 2021 
 
Cohort B only:  
• 
Serum immunoglobulin free light chain ≥5 mg/dL AND abnormal serum 
immunoglobulin kappa to lambda free light chain ratio. 
3.16 
ECOG performance status (PS) 0, 1 or 2 (Appendix VII) 
 
3.17 
Previously untreated.  
 
3.18 
Provide informed written consent. 
 
3.19a 
Negative pregnancy test done ≤7 days prior to registration, for women of 
childbearing potential only. 
 
3.19b Willing to follow strict birth control measures as suggested by the study. 
Female patients: If they are of childbearing potential, agree to one of the 
following: 
• 
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, AND must also adhere to the guidelines of any 
treatment-specific pregnancy prevention program, if applicable, OR  
• 
Agree to practice true abstinence when this is in line with the preferred 
and usual lifestyle of the subject.  (Periodic abstinence [eg, calendar, 
ovulation, symptothermal, post-ovulation methods] and withdrawal are 
not acceptable methods of contraception.) 
Male patients: even if surgically sterilized (ie, status post-vasectomy), must agree 
to one of the following: 
• 
Agree to practice effective barrier contraception during the entire study 
treatment period and through 90 days after the last dose of study drug, 
OR 
• 
Must also adhere to the guidelines of any treatment-specific pregnancy 
prevention program, if applicable, OR 
• 
Agree to practice true abstinence when this is in line with the preferred 
and usual lifestyle of the subject.  (Periodic abstinence (eg, calendar, 
ovulation, symptothermal, post-ovulation methods] and withdrawal are 
not acceptable methods of contraception.) 
 
3.19c 
Willing to return to return to enrolling institution for follow-up (during the 
Active Monitoring Phase of the study). 
 
 
 


 
30  
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Millennium # X16009 
 
 
                     MCCC Add 13 
Protocol Version Date:    February 23, 2021 
 
3.2 
Exclusion Criteria 
 
3.21  
MGUS or smoldering myeloma only. 
 
3.22  
Prior cytotoxic chemotherapy or corticosteroids for the treatment of multiple 
myeloma. NOTE: Prior corticosteroid use for the treatment of non-malignant 
disorders is permitted  
 
3.23 
Diagnosed or treated for another malignancy ≤ 2 years before study enrollment or 
previously diagnosed with another malignancy and have any evidence of residual 
disease.  NOTE: Patients with nonmelanoma skin cancer or carcinoma in situ of 
any type are not excluded if they have undergone complete resection.  
 
3.24 
Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown: 
• 
Pregnant women 
• 
Nursing women  
• 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception 
 
3.25 
Other co-morbidity which would interfere with patient's ability to participate in 
trial, e.g. uncontrolled infection, uncompensated heart or lung disease. 
 
3.26 
Other concurrent chemotherapy, or any ancillary therapy considered 
investigational.  NOTE: Bisphosphonates are considered to be supportive care 
rather than therapy, and are thus allowed while on protocol treatment. 
3.27 
Peripheral neuropathy ≥ Grade 3 on clinical examination or grade 2 with pain 
during the screening period. 
 
3.28 
Major surgery ≤14 days prior to study registration. 
 
3.29a 
Systemic treatment with strong CYP3A4 inducers (rifampin, rifapentine, 
rifabutin, carbamazepine, phenytoin, phenobarbital, Gingko biloba, St. John’s 
wort) ≤14 days prior to registration. 
 
3.29b Evidence of current uncontrolled cardiovascular conditions (NYHA Class III or 
IV), including hypertension, cardiac arrhythmias, congestive heart failure, 
unstable angina, or myocardial infarction within the past 6 months.  Note: Prior 
to study entry, any ECG abnormality at screening must be documented by the 
investigator as not medically relevant. 
 
3.29c 
Radiotherapy  ≤ 14 days prior to registration. NOTE: If the involved field is 
small, 7 days will be considered a sufficient interval between treatment and 
administration of the Ixazomib. 
 
3.29d Known human immunodeficiency virus (HIV) positive. 
 
3.29e 
Known hepatitis B surface antigen-positive status, or known or suspected active 
hepatitis C infection. 


 
31  
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Millennium # X16009 
 
 
                     MCCC Add 13 
Protocol Version Date:    February 23, 2021 
 
 
3.29f 
Any serious medical or psychiatric illness that could, in the investigator’s 
opinion, potentially interfere with the completion of treatment according to this 
protocol. 
 
3.29g Known allergy to any of the study medications, their analogues or excipients in 
the various formulations. 
 
3.29h Known GI disease or GI procedure that could interfere with the oral absorption 
or tolerance of Ixazomib including difficulty swallowing. 
 
3.29i 
Diarrhea > Grade 1, based on the NCI CTCAE grading, in the absence of 
antidiarrheals. 
 
3.29j 
Participation in any other clinical trials with other investigational agents not 
included in this trial, ≤30 days prior to registration.  
 
 
 
 


32  
 
 
MC1382 
Millennium # X16009 
 
 
MCCC Add 12 
 
Protocol Version Date:    February 23, 2021 
 
4.0 
Test Schedule  
 
4.1 Cohort A  
 
Cohort A  
 
Days Prior to Registration 
 
Every 14 days 
 (3 cycles)1 
 
Every cycle, 
pre-
treatment1,11,   
 
Maintenance Phase: 
 
 
≤30 days 
≤14 days 
( every cycle)1, 11 
 
Complete medical history 
X 
 
 
 
 
Adverse Event monitoring 
 
X 
X7 
X13 
X 
Physical exam, including weight and vital 
signs 
 
X 
 
X13 
X 
 
Height 
 
 
 
X 
 
 
 
Performance status (ECOG scale)  
 
X 
X 
X13 
X 
 
CBC with diff. 
 
X 
X 
X13 
X 
Prothrombin time (PT) 
X 
 
 
 
 
Chemistry group to include sodium, 
potassium, glucose, alkaline phosphatase; 
Total and Direct bilirubin; SGOT (AST);ALT 
serum creatinine, calcium 
 
 
X 
 
X 
 
X13 
 
X 
 
LDH, Beta2-microglobulin, C-reactive protein, 
Plasma cell assessment 
X 
 
 
 
 
Electrophoresis of serum and urine 
 
X 
 
X12 
X12 
Affected Immunoglobulin 
 
X 
 
X9 
X9 
Immunofixation serum and urine 
X 
 
  
X2 
X2 
Immunoglobulin free light chain 
 
X 
 
X5 
X5 
X-ray skeletal survey 
X 
 
 
X4 
X 4 
 


33  
 
 
MC1382 
Millennium # X16009 
 
 
MCCC Add 12 
 
Protocol Version Date:    February 23, 2021 
 
Bone marrow aspirate and biopsy, myeloma 
FISH, metaphase cytogenetics, plasma cell 
proliferation, and flow cytometry.   
X 
 
 
X6 
X6 
 
Research bone marrow and blood sample as 
per 521-93, optionalR 
 
X 
 
 
X6 
X6 
 
Chest x-ray 
X 
 
 
 
 
Pharmacokinetics (see schedule below) 
 
 
 
 
 
Serum pregnancy test 
 
X3 
 
 
 
Patient Medication Diary (Appendix IV)8 
 
 
 
X 
X 
FACT/GOG neurotoxicity questionnaire 
(Appendix V) 
 
X 
 
X10 
X10 
 
1) All scheduled visits will have a window of ± 4 days unless otherwise stated 
2) Immunofixation (IF) needed only in the absence of M-spike to document CR or sCR. 
3) For women of childbearing potential only.  Must be done ≤7 days prior to registration. 
4) Every 6 cycles. 
5)    FLC is required only if used to assess disease response during active phase 
6)   At the end of 4 and 12 cycles and only required to document CR after that. If a bone marrow was done to confirm CR prior to end of 12 
cycles, no further bone marrow examination is required. 
7)   Every 14 days times 3 cycles then monthly thereafter during induction treatment;   
8)  The diary must begin the day the patient starts taking the medication and must be completed per protocol and returned to the treating 
institution. 
9)  Affected immunoglobulin refers to the baseline M-protein type, that is, IgG, IgA, or IgD.  Not applicable if patient “non-secretory” or if 
patient has no heavy chain, i.e. light chain myeloma. .  Affected immunoglobulin is required after baseline only if it used for disease 
monitoring instead of SPEP (for e.g. IgA myeloma) 
10)  The FACT/GOG neurotoxicity questionnaire will be filled out by the patient at baseline, every cycle for the first 4 cycles, and then 
every 3 cycles (+/- 1 cycle). 
11)  During the induction phase, patients should return every cycle for the first 4 cycles, and then can return every two cycles provided the 
required laboratory evaluations can be obtained and toxicity assessments can be performed over the phone. During maintenance phase 
patients can return every three cycles provided the required laboratory evaluations can be obtained and toxicity assessments can be 
performed over the phone.  
12)  Urine Electrophoresis required only if used to assess disease response 
13)  Does not need to be repeated at Cycle 1 Day 1. Baseline values can be used for cycle 1. 
R  Research funded (see Section 19.0).  Will be charged to study and not to patient’s account. 
 


34  
 
 
MC1382 
Millennium # X16009 
 
 
MCCC Add 12 
 
Protocol Version Date:    February 23, 2021 
 
4.2 Cohort B 
   
Cohort B 
 
Days Prior to 
Registration 
 
Every 14 
days 
 (3 cycles)1 
 
Every cycle, 
pre-treatment1,9  
 
Maintenance 
Phase: 
 
 
≤30 days 
≤14 days 
( every cycle)1,9 
 
Complete medical history 
X 
 
 
 
 
Adverse Event monitoring 
 
X 
X6 
X11 
X13 
Physical exam, including weight and vital signs 
 
X 
 
X11 
X13 
Height 
 
 
 
X 
 
 
 
Performance status (ECOG scale) and NY Heart Association Class 
 
X 
X 
X11 
X13 
CBC with diff.  
 
X 
X 
X11 
X13 
Prothrombin time (PT)/INR, APTT 
X 
 
 
 
 
Factor X chromogenic activity assay  
X  
 
 
 
 
Chemistry group to include sodium, potassium, glucose, alkaline 
phosphatase; Total and Direct bilirubin; AST; ALT; uric acid; 
serum creatinine, calcium  
 
 
X 
 
X 
 
X11 
 
X13 
 
Cardiac troponin-T, NTProBNP,  
X 
 
 
X12 
X12,13 
ECHO with strain; Ejection fraction (obtain using 
echocardiogram) 
X 
 
 
X12 
X12,13 
Electrophoresis of serum and urine (24 hour) 
 
X 
 
X10 
X10,13 
Affected Immunoglobulin 
 
X 
 
X8 
X8,13 
Immunofixation serum and urine 
X 
 
  
X2 
X2,13 
Immunoglobulin free light chain 
 
X 
 
X  
X 13 
Bone marrow aspirate and biopsy, plasma cell proliferation   
X 
 
 
X5 
X5 
 
Research bone marrow and blood sample as per 521-93, optionalR 
X 
 
 
X5 
X5 
Chest x-ray 
X 
 
 
 
 
Serum pregnancy test 
 
X3 
 
 
 
24-hour creatinine clearance  
X 
 
 
X12 
X12 
Abdominal non-contrast CT 
X 
 
 
X12 
X12 


35  
 
 
MC1382 
Millennium # X16009 
 
 
MCCC Add 12 
 
Protocol Version Date:    February 23, 2021 
 
Nerve conduction studies (only nerve involvement that will be 
followed by response), including  compound muscle action 
potential (CMAP) 
X 
 
 
X12 
X12 
Neurology consult for Nerve Impairment Score (only nerve 
involvement that will be followed for response) 
X 
 
 
X12 
X12 
Patient Medication Diary (Appendix IV)7 
X 
 
 
X 
X 
FACT/GOG neurotoxicity questionnaire (Appendix V) 
 
X 
 
X14 
X14 
 
1) All scheduled visits will have a window of ± 4 days unless otherwise stated. 
2) Immunofixation (IF) needed only in the absence of M-spike to document CR or sCR. 
3) For women of childbearing potential only.  Must be done ≤7 days prior to registration. 
4) Every 6 cycles. 
5) At the end of 4 and 12 cycles and only required to document CR after that. If a bone marrow was done to confirm CR prior to end of 12 
cycles, no further bone marrow examination is required. 
6) Every 14 days times 3 cycles then monthly thereafter during induction treatment. 
7) The diary must begin the day the patient starts taking the medication and must be completed per protocol and returned to the treating 
institution. 
8) Affected immunoglobulin refers to the baseline M-protein type, that is, IgG, IgA, or IgD.  Not applicable if patient “non-secretory” or if 
patient has no heavy chain, i.e. light chain myeloma. Affected immunoglobulin is required after baseline only if it used for disease monitoring 
instead of SPEP (for e.g. IgA myeloma). 
9) During the induction phase, patients should return every cycle for the first 4 cycles, and then can return every two cycles provided the required 
laboratory evaluations can be obtained and toxicity assessments can be performed over the phone. During maintenance phase patients can 
return every three cycles provided the required laboratory evaluations can be obtained and toxicity assessments can be performed over the 
phone.  
10) Urine Electrophoresis required only if used to assess disease response. 
11) Does not need to be repeated at Cycle 1 Day 1. Baseline values can be used for cycle 1. 
12) Do only to follow organ involvement and response (e.g. EMG for peripheral nerve, CT or US for liver).  Not needed in all patients. 
13) Required evaluations can be done through local facility, phone contact, or by local lab as applicable 
14) The FACT/GOG neurotoxicity questionnaire will be filled out by the patient at baseline, every cycle for the first 4 cycles, and then every 3 
cycles (+/- 1 cycle). 
R Research funded (see Section 19.0).  Will be charged to study and not to patient’s account. 
 
 


36  
 
 
MC1382 
Millennium # X16009 
 
 
MCCC Add 12 
 
Protocol Version Date:    February 23, 2021 
 
 
Table 4.2 Cohort A only: Pharmacokinetic sampling  
Cycle 1 
Cycle2 
Day 1 
Day 8 
Day 15 
Day 22 
Day1 
(Post-dose) Hours 
 
1 (+/-0.25) 
4 (+0.75) 
Predose 
(within 1 
hour of 
dosing) 
Predose 
(within 1 
hour of 
dosing) 
No dose 
given, PK 
can be 
drawn at 
anytime 
Predose 
(within 1 
hour of 
dosing) 
X 
X 
X 
X 
X 
X 


 
37  
 
 
 MC1382 
Millennium # X16009 
 
 
MCCC Add 12 
 
Protocol Version Date:    February 23, 2021 
 
5.0 
Grouping Factor:  
 
5.1   Phase:  I vs. II 
 
5.2  Cohort:  A (multiple myeloma) vs. B (light chain amyloidosis) 
 
6.0  
Registration/Randomization Procedures 
6.1 
Phase I 
 
Prior to discussing protocol entry with the patient, call the MCCC Registration 
Office 
for dose level and to insure that a place on the protocol is 
open to the patient.  
 
6.11 
Registration Procedures 
 
6.111 To register a patient, fax 
a completed eligibility checklist 
to the Mayo Clinic Cancer Center (MCCC) Registration Office between 
8 a.m. and 4:30 p.m. central time Monday through Friday.   
6.2 
Phase II 
 
6.21  
Registration Procedures 
 
To register a patient, access the Research Registration Application at 
.  The Research Registration Application is available 24 
hours a day, 7 days a week. Back up and/or system support contact information is 
available on the Web site. If unable to access the application, call the Mayo 
Clinic Site Management Team at 
 between the hours of 8 a.m. 
and 4:30 p.m. Central Time (Monday through Friday) or email them at 
 Quick Reference Guides (QRGs) for the 
application are available to study staff on the Mayo Clinic Office of Clinical 
Trials, Site Management Team website.  
Prior to initiation of protocol treatment, this process must be completed in its 
entirety and a MCCC patient  ID number must be provided The patient ID will 
begin with an ‘R’ and will be followed by 8 digits. It is the responsibility of the 
individual registering the patient to confirm the process has been successfully 
completed prior to release of the study agent. Patient registration via the 
Research Registration Application can be confirmed in any of the following 
ways: 
• 
Contact the Mayo Clinic Site Management Team. If the patient was fully 
registered, the MCCC Registration Office staff can access the 
information from the centralized database and confirm the registration. 


 
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• 
View your list of registered patients via the Accruals Tile on the Patient 
Landing page of the Research Registration Application.  
 
 
6.211 Documentation of IRB approval must be on file with the Site 
Management team before an investigator may register any patients.  
In addition to submitting initial IRB approval documents, ongoing IRB 
approval documentation must be on file (no less than annually) at the 
Registration Office 
). If the necessary documentation 
is not submitted in advance of attempting patient registration, the 
registration will not be accepted and the patient may not be enrolled in 
the protocol until the situation is resolved. 
 
When the study has been permanently closed to patient enrollment, 
submission of annual IRB approvals to the Site Management Team is no 
longer necessary. 
 
6.212 Verification 
 
Prior to accepting the registration, the Registration Application will 
verify the following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of 
protected health information  
 
 
6.3 
Phase I and II 
 
6.31 
Correlative Research: (See section 14) 
 
6.32 
 
6.33 
At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her sample(s) for 
future research of Multiple Myeloma at Mayo. 
• 
Patient has/has not given permission to store and use his/her sample(s) for 
future research to learn, prevent, or treat other health problems. 
• 
Patient has/has not given permission for MCCC to give his/her sample(s) to 
researchers at other institutions. 
 
6.34 
Cohort A: Treatment on this protocol must commence at Mayo Clinic Rochester 
or Mayo Clinic Arizona, under the supervision of a hematologist. 
 
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Cohort B: Treatment on this protocol must commence under the supervision of a 
hematologist from the enrolling institution.  
 
6.35 
Treatment cannot begin prior to registration and must begin ≤ 14 days after 
registration. 
 
6.36 
Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
 
6.37 
All required baseline symptoms (see Section 10.51) must be documented and 
graded. 
 
6.38 
Study drug is available on site.  
 
6.4 
The clinical trial will be conducted in compliance with regulations (21 CFR 312, 50, and 
56), guidelines for Good Clinical Practice (ICH Guidance E6), and in accordance with 
general ethical principles outlined in the Declaration of Helsinki; informed consent will 
be obtained from all participating patients; the protocol and any amendments will be 
subject to approval by the designated IRB prior to implementation, in accordance with 21 
CFR 56.103(a); and subject records will be stored in a secure location and subject 
confidentiality will be maintained. The investigator will be thoroughly familiar with the 
appropriate use of the study drug as described in the protocol and Investigator’s 
Brochure.  Essential clinical documents will be maintained to demonstrate the validity of 
the study and the integrity of the data collected.  Master files should be established at the 
beginning of the study, maintained for the duration of the study and retained according to 
the appropriate regulations.   
 
 
7.0 
Protocol Treatment 
 
 
 
7.1 
Treatment Schedule - Use actual weight or estimated dry weight if fluid retention 
  
PHASE 1 INDUCTION (Cycles 1-12) 
Agent 
Dose Level 
Route 
Day 
Retreatment 
Ixazomib* 
As assigned by 
MCCC 
Registration 
Office 
 
PO 
1, 8, 15 
Every 28 
days 
Cyclophosphamide 
PO 
1, 8, 15, 22 
Every 28 
days 
Dexamethasone 
PO 
1, 8, 15, 22 
Every 28 
days 
 
 


 
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Cohort A:  PHASE 2 INDUCTION (Cycles 1-12) 
Agent 
Dose Level 
Route 
Day 
Retreatment 
Ixazomib* 
Based on phase 
I results 
PO 
1, 8, 15 
Every 28 
days 
Cyclophosphamide 
PO 
1, 8, 15, 22 
Every 28 
days 
Dexamethasone 
PO 
1, 8, 15, 22 
Every 28 
days 
 
 
Cohort B: PHASE 2 INDUCTION (Cycles 1-12) 
Agent 
Dose Level 
Route 
Day 
Retreatment 
Ixazomib* 
4 mg 
PO 
1, 8, 15 
Every 28 
days 
Cyclophosphamide 
500 mg 
PO 
1, 8, 15, 22 
Every 28 
days 
Dexamethasone 
40 mg 
PO 
1, 8, 15, 22 
Every 28 
days 
 
 
 
 
 
 
 
MAINTENANCE (All patients) 
Ixazomib* 
Phase 2 dose 
(continue with 
same dose as 
cycle 12) 
PO 
1, 8, 15 
Every 28 
days**  
*The study drug should be taken on an empty stomach, at least 1 hour before or at least 2 hours 
food.  Each capsule should be swallowed separately with a sip of water.  A total of approximately 
240 mL of water should be taken with the capsules 
** Treatment will continue till disease progression, unacceptable toxicity, withdrawal of consent, 
or if patient and/or physician prefer to discontinue therapy. 
 
 
7.2 
The doses of Ixazomib used in this study are based on data from Millennium’s ongoing 
phase 1 trials. In these trials the dose of Ixazomib was based on BSA. A population PK 


 
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analysis was performed for Ixazomib to assess the feasibility of switching from BSA-
based dosing to flat dosing. A population PK model was built using nonlinear mixed 
effects modeling in NONMEM VII software compiled with the Intel Fortran 9.2 
compiler. Data from both the twice-weekly and once-weekly IV dosing regimens were 
used in the analysis (N = 42). Population PK analysis showed that Ixazomib PK can be 
well described by a 3- compartment model with linear elimination. Race, sex, BSA, 
and/or body weight do not appear to significantly affect clearance (CL) and volume of 
distribution (V1) in the central compartment. Clearance and volume of distribution in the 
central compartment are the PK parameters that will affect AUC and Cmax, respectively. 
CL and V1 are primary parameters that are independent of the route of administration of 
drug. Therefore, BSA is not expected to affect Cmax or AUC after oral dosing, and thus 
flat dosing is appropriate for both oral and IV routes of administration.  
 
 
7.3  
Patients should be instructed to swallow Ixazomib capsules whole, with water, and not to 
break, chew, or open the capsules.  The study drug should be taken on an empty stomach, 
at least 1 hour before or at least  2 hours after food.  Each capsule should be swallowed 
separately with a sip of water.  A total of approximately 8 ounces (240 mL) of water 
should be taken with the capsules.   
 
The prescribed administration of Ixazomib doses in this study is the MTD of Millennium 
study C16004 weekly in a 28-day cycle.  Missed doses can be taken as soon as the patient 
remembers as long as 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. 
 
Drug will be administered only to eligible patients under the supervision of the 
investigator or identified subinvestigator(s).  Patients may be treated on an outpatient 
basis, if possible. 
 
The drug will be prepared under the supervision of a pharmacist, or appropriately 
qualified and trained personnel. 
 
7.4 
Cohort A:  
 
For cohort A the patient must be evaluated at the consenting institution (Mayo Clinic) as 
described in the Test Schedule (Section 4).  Treatment by a local medical doctor (LMD) 
is not allowed.   
 
 
Cohort B (as of amendment 12) 
 
For cohort B, the patient must return to the consenting institution for evaluation at least 
every third cycle, provided the drug can be sent to the patient and necessary interval 
evaluations as required by the protocol can be completed remotely or through local 
healthcare facilities 
 
7.5 
Patients are allowed to collect stem cells any time after 3 cycles of initial therapy. 
Therapy may be interrupted for up to 4 weeks for the purpose of stem cell collection. 
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collection is completed, patients will initiate next cycle of therapy and continue as per 
protocol. Any delay beyond 4 weeks should be discussed with the study PI prior to 
reinitiating protocol therapy. Patients can go off study treatment for stem cell 
transplantation any time after 6 cycles of therapy. Patients who discontinue therapy for 
stem cell transplantation will go to event monitoring phase of the study and will not get 
any additional therapy with Ixazomib. 
 
7.6 
Phase I – determination of Maximum Tolerated Dose (MTD)  
 
7.51 
Dose Escalation for individual drugs 
 
Dose 
level 
Ixazomib 
(Days 1, 8, 
15) 
Cyclophosphamide 
(Days 1, 8, 15, 22) 
Dexamethasone 
(Days 1, 8, 15, 
22) 
-2 
3 mg 
200 mg/m2 
12 mg 
-1 
4 mg 
200 mg/m2 
20 mg 
0* 
4 mg 
300 mg/m2 
40 mg 
+1 
4 mg 
400 mg/m2 
40 mg 
 
 
*starting dose level  
 
 
7.611 Treatment by a local medical doctor is not allowed. 
 
7.612  Three patients will be treated at each dose level and observed for a 
 
minimum of 28 days, to assess toxicities, before new patients are treated. 
The study will temporarily close.  Doses will not be escalated in any 
individual patient. 
 
 
 
 
7.613 Investigators are to contact the Study Chair as soon as any dose-limiting 
toxicity (DLT) occurs. 
 
7.62 
Definitions of DLT 
 
7.621 For this protocol, dose-limiting toxicity (DLT) will be defined as an 
adverse event attributed (definitely, probably, or possibly) in the first 
cycle to the study treatment and meeting the following criteria: 
 
 
 
Toxicity* 
DLT Definition 
Investigations 
Grade 4 neutropenia (ANC < 500/mm3) for ≥7 days 
or Grade 4 thrombocytopenia  (<25,000/mm3) for 
≥7 days 
Infection and infestations 
Grade 4 
Blood and lymphatic system 
disorders 
Defined as fever ≥ 38.5oC (38 > 1 hour) with grade 
≥ 3 neutropenia 
Other Non-hematologic 
≥ Grade 3 as per NCI Common Terminology 


 
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Criteria for Adverse Events v 4.0**.  
Dose Delay 
Any toxicity that causes a dose delay of > 2 weeks 
of the next intended dose  
Dose Reduction 
Any dose reduction within cycle 1 
 
                                      
                                     * Adverse event at least possibly related to the study medication.  
 
**Grade 3 nausea, vomiting, or diarrhea with maximal supportive treatment(s) 
will be considered dose limiting.  Fatigue and mouth sores that are considered 
Grade 3 with an attribution of definitely, probably, or possibly related to treatment 
will be reviewed by the study team to determine if they were due to other causes 
(i.e. disease progression or infection) or treatment.   If it is determined that the 
fatigue or mouth sores were due to other causes they would not be considered a 
DLT and if they were due to treatment they would be considered a DLT. 
 
 
8.0 
Dosage Modification Based on Adverse Events  
 
Strictly follow the modifications in this table for the first two cycles, until individual treatment 
tolerance can be ascertained.  Individual drugs can be dose reduced as per the table below 
depending on the adverse event attribution. Thereafter, these modifications should be regarded as 
guidelines to produce mild-to-moderate, but not debilitating, side effects.  If multiple adverse 
events are seen, administer dose based on greatest reduction required for any single adverse event 
observed.  Reductions apply to treatment given in the preceding cycle and are based on adverse 
events observed since the prior dose. 
 
 
 
ALERT: 
ADR reporting may be required for some adverse events (See Section 10) 
 
8.1  
Dose Levels for each drug in the combination. The same dose modification schema will 
be used for Ixazomib in the maintenance phase (Based on Adverse Events in Tables 8.2  
and 8.3) 
 
Cohorts A and B 
Ixazomib 
(Days 1, 8, 15) 
Starting 
dose 
4 mg 
  
-1 
3 mg 
  
-2 
2.3 mg 
  
-3 
2.3 mg days 1, 15 
  


 
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Cohorts A and B 
Ixazomib 
(Days 1, 8, 15) 
-4 
Discontinue 
 
If patients cannot tolerate dose level – 3 of Ixazomib they will go to event monitoring. 
 
 
 
Cohort A 
Cyclophosphamide 
(Days 1, 8, 15, 22) 
 
 
 
 
 
Starting 
dose 
400 mg/m2 
300 mg/m2 
200 mg/m2 
100 mg/m2 
-1 
300 mg/m2 
200 mg/m2 
100 mg/m2 
Discontinue 
-2 
200 mg/m2 
100 mg/m2 
Discontinue 
 
-3 
100 mg/m2  
Discontinue 
 
 
-4 
Discontinue 
 
 
 
 
Cohort B 
Cyclophosphamide  
 
(Days 1, 8, 15, 22) 
Starting dose 
500 mg 
-1 
400 mg 
-2 
200 mg 
-3 
Discontinue 
 
 
 
Cohorts A and  B 
Dexamethasone 
(Days 1, 8, 15, 22) 
Starting 
dose 
40 mg 
20 mg 
-1 
20 mg 
12 mg 
-2 
12 mg 
4  mg  
-3 
4 mg  
Discontinue 
-4 
Discontinue 
 


 
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Note:  If Ixazomib is discontinued, the patient will go to event monitoring per 
Section 18.0.  If cyclophosphamide and/or dexamethasone are discontinued, the 
patient may continue treatment. 
 
 
8.11  
Instruction for initiation of a new cycle of therapy  
A new cycle of treatment may begin on the scheduled Day 1 of a new cycle if: 
• 
The ANC is ≥ 1000/μL 
• 
The platelet count is ≥ 75,000/μL 
• 
Any other non-hematologic Ixazomib-related adverse event that may have 
occurred has resolved to ≤ Grade 1 or baseline severity. 
If these conditions are not met on Day 1 of a new cycle, 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.   
If any drug dosing was halted during the previous cycle and was restarted 
with a one-level dose reduction without requiring an interruption for the 
remainder of the cycle, then that reduced dose level will be initiated on Day 1 
of the new cycle.  
If any drug dosing was omitted for the remainder of the previous cycle or if 
the new cycle is held due to known hematologic toxicity newly encountered 
on the scheduled Day 1, then the new cycle will be started with a one-level 
dose reduction.  If a new cycle of therapy cannot be restarted within 4 weeks 
of the scheduled Day 1 due to non-resolution of drug related toxicities, the 
patient will be removed from protocol therapy and will go to event 
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8.2  
Dose modifications based on adverse events during a cycle 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT# 
 
ACTION** 
BASED ON INTERVAL ADVERSE EVENT (Days 2-28 of each cycle) 
Investigations 
If platelet count ˂ 30 × 
109/L or ANC ˂1.0 × 
109/L or ANC > 1.0 × 
109/L (up to LLN) with 
fever (temperature 
> 38.5°C) 
Ixazomib 
Days 2-15: Ixazomib dose should be 
omitted.  Complete blood count (CBC) 
with differential should be followed 
weekly. If ANC is > 1.0 × 109/L and/or 
platelet counts > 30 × 109/L, Ixazomib 
may be reinitiated with 1 dose level 
reduction (see table 8.1). The subsequent 
cycle will use the reduced dose.  If a 
patient is already at the lowest drug level, 
go to event monitoring. 
Skin and 
subcutaneous tissue 
disorders 
Rash, maculopapular, 
≥Grade 2 
Ixazomib 
Omit IxazomiB till rash resolves to ≤ 
Grade 1 (See Section 9.9b).  Restart at 
same dose. If the rash recurs, reduce dose 
by one dose level.  If a patient is already 
at the lowest drug level, go to event 
monitoring. 
Any skin, Grade 4 
Ixazomib 
Discontinue Ixazomib and go to event 
monitoring 
Nervous System 
Disorders 
New or worsening 
Grade 1 peripheral 
neuropathy with pain, ≥ 
Grade 2 peripheral 
neuropathy, 
Ixazomib 
Omit Ixazomib until resolution to Grade ≤ 
1 or baseline 
Grade 2 neuropathy 
with pain or Grade 3 
peripheral neuropathy 
Ixazomib 
Omit Ixazomib until toxicity resolves to < 
Grade 1 or returns to baseline.  When 
toxicity resolves, re-initiate Ixazomib at 
the next lower dose level.  If a patient is 
already at the lowest drug level, go to 
event monitoring. 
Grade 4 peripheral 
neuropathy 
Ixazomib 
Permanently discontinue Ixazomib. 
Genitourinary 
Cystitis > grade 2 
Cyclophos
phamide 
Omit cyclophosphamide until toxicity 
resolves or returns to baseline.  When 
toxicity resolves, re-initiate 
cyclophosphamide at the next lower dose 
level.   


 
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  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT# 
 
ACTION** 
Other 
Any other non-
hematological Grade 3 
attributable toxicity 
except: 
> Grade 3 nausea 
and/or emesis in the 
absence of optimal anti-
emetic prophylaxis  
 
> Grade 3 diarrhea that 
occurs in the absence of 
optimal supportive 
therapy  
 
≥ Grade 3 fatigue 
Ixazomib 
Cyclophos
phamide 
Omit Ixazomib or cyclophosphamide or 
both depending on the attribution to either 
or both drugs, until resolution to Grade < 
1 or baseline.  , hold both drugs.  Restart 
at next lower dose.  If a patient is already 
at the lowest drug level, go to event 
monitoring.  
If the toxicity can be attributed to either 
of the drugs, cyclophosphamide should be 
discontinued at first instance followed by 
Ixazomib for recurrence of the same 
toxicity necessitating dose modification. 
 
Grade 4 
Nonhematologic 
Toxicities 
Ixazomib 
Permanently discontinue 
cyclophosphamide.  
Consider permanently discontinuing 
Ixazomib.  Exception, in the case where 
the investigator determines the patient is 
obtaining a clinical benefit. 
 
* 
Located at http:/ctep.cancer.gov/protocolDevelopment/electronic applications.ctc.htm 
**  Use the following to describe actions in the Action column: 
 Omit = The current dose(s) for the specified drug(s) during a cycle is skipped.  The patient 
does not make up the omitted dose(s) at a later time 
 Hold/Delay = The current dose(s) of all drugs during a cycle is delayed. The patient does 
make up the delayed dose(s) when the patient meets the protocol criteria to restart drugs. 
 Discontinue = The specified drug(s) are totally stopped. 
 
# 
NOTE: For toxicities attributable to both Ixazomib and cyclophosphamide, only one of the drugs 
should be reduced for each incidence of toxicity severe enough to necessitate dose reduction. The drug 
reduced should alternate starting with cyclophosphamide for the first dose reduction. 
 
8.3  
Dose modifications for dexamethasone based on adverse events during a cycle 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   


 
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CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
BASED ON INTERVAL ADVERSE EVENT (Days 2-28 of each cycle) 
Gastrointestinal 
disorders 
Dyspepsia, gastric or 
duodenal ulcer, gastritis 
Grade 1-2 
(Symptomatic; altered 
GI function; medical 
intervention indicated; 
limiting instrumental 
ADL ) 
Dexamethasone 
Treat with H2 blockers, sucralfate, 
or omeprazole. If symptoms persist 
despite above measures, decrease 
dexamethasone dose by 1 dose 
level.   
 
Dyspepsia, gastric or 
duodenal ulcer, gastritis 
≥Grade 3 (Severely 
altered GI function; TPN 
indicated; elective 
operative or endoscopic 
intervention indicated; 
limiting self-care ADL; 
disabling) 
Dexamethasone 
Omit dexamethasone until 
symptoms adequately controlled. 
Restart one dose level below along 
with concurrent therapy with H2 
blockers, sucralfate, or omeprazole. 
If symptoms persist despite above 
measures, discontinue 
dexamethasone and do not resume.  
Ixazomib should be continued. 
 
Pancreatitis 
≥ Grade 3 (Severe pain; 
vomiting; medical 
intervention indicated 
(e.g., analgesia, 
nutritional support)) 
Dexamethasone 
Discontinue dexamethasone and do 
not 
Resume.  Ixazomib should be 
continued 
General disorders 
and administration 
site conditions 
Edema 
≥ Grade 3 (limiting 
function and 
unresponsive to therapy 
or anasarca) 
Dexamethasone 
Diuretics as needed, and decrease 
dexamethasone dose by 1 dose 
level; if edema persists despite 
above measures, decrease dose 
another dose level. Discontinue 
dexamethasone and do not resume 
if symptoms persist despite second 
reduction.  Ixazomib should be 
continued. 
Psychiatric disorders 
Confusion or Mood 
alteration 
≥ Grade 2 (Severe 
disorientation; limiting 
self-care ADL) 
Dexamethasone 
Omit dexamethasone until 
symptoms resolve. Restart with one 
dose level reduction. If symptoms 
persist despite above measures, 
discontinue dexamethasone and do 
not resume.  Ixazomib should be 
continued. 


 
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  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
Musculoskeletal and 
connective tissue 
disorders 
Muscle weakness 
≥ Grade 2  
 Weakness limiting self 
care ADL; disabling 
Dexamethasone 
Decrease dexamethasone dose by 
one dose level; if weakness persists 
despite above measures decrease 
dose by one additional dose level. 
Discontinue dexamethasone and do 
not resume if symptoms continue to 
persist.  Ixazomib should be 
continued. 
Metabolism and 
nutrition disorders 
Hyperglycemia Grade 3 
or higher, (>250 - 500 
mg/dL; >13.9 - 27.8 
mmol/L); hospitalization 
indicated 
Dexamethasone 
Treatment with insulin or oral 
hypoglycemics as needed. If 
uncontrolled despite above 
measures, decrease dose by one 
dose level at a time until levels are 
satisfactory. 
* 
Located at http:/ctep.cancer.gov/protocolDevelopment/electronic applications.ctc.htm 
**  
Use the following to describe actions in the Action column: 
 Omit = The current dose(s) for the specified drug(s) during a cycle is skipped.  The patient 
does not make up the omitted dose(s) at a later time 
 Hold/Delay = The current dose(s) of all drugs during a cycle is delayed. The patient does 
make up the delayed dose(s) when the patient meets the protocol criteria to restart drugs. 
 Discontinue = The specified drug(s) are totally stopped. 
 
NOTE:  Adverse events requiring a dose-reduction step for any or all drugs beyond the three dose-
reduction steps (levels -1, -2 and -3) will be at the discretion of the Principal Investigator, if the 
decision is made for the patient to be kept on study.  These dose reductions must be clearly 
recorded in reported clinical data.  
 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Patients may receive concurrent treatment with a bisphosphonate.  
 
9.2 
Patients may continue on low level/stable steroid doses for replacement or inhalation 
therapy. 
 
9.3 
The following medications are not permitted during the trial: 
• 
Any other investigational treatment  
• 
Any other systemic anti-neoplastic therapy including, but not limited to, 
immunotherapy, hormonal therapy or monoclonal antibody therapy. 
• 
Any external beam radiotherapy 


 
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• 
Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 
days  prior to study drug dosing for any dosing day 
9.4 
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. 
 
9.5 
Granisetron should be given prior to Ixazomib for prophylaxis. Additional antiemetics 
may be used at the discretion of the attending physician. Dexamethasone should not be 
administered as an anti-emetic. Volume depletion should be corrected before initiation of 
study drug. 
 
9.6 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations.  The use of growth factors should 
follow published guidelines of the Journal of Clinical Oncology, Vol 24, No 18 (June 
20), 2006: pp. 2932-2947 
 
9.7 
Patients should receive full supportive care while on this study.  This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions.  All blood products and concomitant medications such 
as antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the 
medical records. 
 
9.8 
Diarrhea:  This can be managed conservatively with loperamide.  The recommended dose 
of loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea free 
(maximum 16 mg/day). 
 
In the event of Grade 3 or 4 diarrhea, the following supportive measures are allowed:  
hydration, octreotide, and antidiarrheals.   
 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (Grade 3 or 4), broad-spectrum antibiotics must be prescribed.  
Patients with severe diarrhea or any diarrhea associated with severe nausea or vomiting 
should be hospitalized for intravenous hydration and correction of electrolyte 
imbalances. 
 
9.9a  
Two cases of acute renal failure have been reported in patients treated at or above the 
MTD for intravenous Ixazomib (see Section 1.4.3).  Volume depletion should be 
corrected before initiation of study drug.  Until further information is available, intake of 
nonsteroidal anti-inflammatory drugs immediately prior to the administration of 
Ixazomib should be discouraged and requires consultation with the principle investigator. 


 
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All necessary supportive care consistent with optimal patient care shall be available to 
patients as necessary. 
 
9.9b 
Herpes Zoster prophylaxis with acyclovir 400 mg PO BID should be used while on study 
therapy and for 1 month beyond the end of therapy 
 
  
9.9c 
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:  If there were to be a drug-drug interaction with an inducer, Ixazomib 
exposure would be decreased. -   
 
• 
Strong CYP3A inducers: rifampin, rifapentine, rifabutin, carbamazepine, 
phenytoin, and phenobarbital 
 
Excluded foods and dietary supplements include St. John’s wort and Ginkgo biloba. 
 
The following procedures are prohibited during the study. 
• 
Participation in clinical trials with other investigational agents, not included 
in this trial, within 14 days of the start of this trial and throughout the 
duration of this trial. 
• 
Any antineoplastic treatment with activity against MM except for drugs in 
this treatment regimen. 
• 
Radiation therapy (the requirement for local radiation therapy generally 
indicates disease progression). 
• 
Platelet transfusions to help patients meet eligibility criteria are not allowed 
within 3 days before study drug dosing. 
• 
Adjuvant hormone therapy for breast or prostate cancer. 
 
9.9d      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 (eg, prednisone ≤ 10 mg per day or 
equivalent) is permitted.  Management of a Grade 3 rash may require intravenous 
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agent if given in combination) should be modified per protocol and re-initiated at a 
reduced level from where rash was noted (also, per protocol).   
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 (eg, 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. 
 
9.9e 
Thrombocytopenia 
Thrombocytopenia has been reported to date primarily at the higher doses tested.  Blood 
counts should be monitored regularly as outlined in the protocol with additional testing 
obtained according to standard clinical practice.  Thrombocytopenia may be severe but 
has been manageable with platelet transfusions according to standard clinical practice. 
Thrombocytopenia nadirs commonly recover without intervention by the beginning of the 
next scheduled cycle. Ixazomib administration should be modified as noted as per dose 
modification recommendations in Table 6-2 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. 
 
9.9f 
Neutropenia 
Neutropenia has been reported with Ixazomib.  Blood counts should be monitored 
regularly as outlined in the protocol with additional testing obtained according to 
standard clinical practice.  Neutropenia may be severe but has been manageable with 
G-CSF according to standard clinical practice.  Neutropenic nadirs commonly recover 
without intervention by the beginning of the next scheduled cycle or with a short delay in 
treatment.  Ixazomib administration should be modified when neutropenia occurs, as 
noted in the dose modification recommendations in Table 6-2.  Therapy can be reinitiated 
at a reduced level upon recovery of absolute neutrophil counts. 
 
9.9g 
Fluid Deficits 
Dehydration should be avoided because Ixazomib may cause vomiting, diarrhea, and 
dehydration.  Acute renal failure has been reported with Ixazomib.  Fluid deficits should 
be corrected before initiation of study drug and during treatment and as needed during 
therapy.  Until further information is available, intake of NSAIDs while on this protocol 
should be avoided. 


 
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9.9h 
Hypotension 
 
Symptomatic hypotension and orthostatic hypotension 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 (for either hypo- or 
hypertension) should be managed according to standard clinical practice, including 
considerations for dose adjustments of their concomitant medications during the course 
of the trial.  
 
 
9.9i 
Posterior Reversible Encephalopathy Syndrome  
One case of posterior reversible encephalopathy syndrome (PRES) has been reported 
with IXAZOMIB.  While this case ultimately resolved, PRES has also been reported 
rarely with another proteasome inhibitor, VELCADE.  PRES is characterized by 
headache, seizures and visual loss, as well as abrupt increase in blood pressure.  Prompt 
diagnosis and initiation of antihypertensive and anticonvulsant therapy are important to 
prevent irreversible end-organ damage. 
9.9j 
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 Ixazomib may have contributed to transverse myelitis cannot be 
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as serious AE which is defined in the table in Section 10.4. 
 
10.2  
Expected vs. Unexpected Events  
 
• 
The determination of whether an AE is expected is based on agent-specific 
information provided in Section 15.0 of the protocol and the study specific 
consent form. 
 
• 
Unexpected AEs are those not listed in the agent-specific information 
provided in Section 15.0 of the protocol and the study specific consent form. 
 
NOTE: “Unexpected adverse experiences” means any adverse experience that is neither 
identified in nature, severity, or frequency of risk in the information provided for IRB 
review nor mentioned in the consent form.  
 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal relationship 
between the drug and the adverse event.  
 
10.31  AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) on 
the SAME Arm 
 
NOTE:  When a commercial agent(s) is (are) used on the same 
treatment arm as the investigational agent/intervention (also, 
investigational drug, biologic, cellular product, or other 
investigational therapy under an IND), the entire combination (arm) is 
then considered an investigational intervention for reporting. 
 
Routine Reporting 
 
• Routine AE reporting for Phase 1 and Phase 2 clinical studies using an 
investigational agent /intervention in combination with a commercial agent 
is stated in the protocol.  See Section 10.6. 
 


 
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• Routine AE reporting for Phase 3 clinical studies using an investigational 
agent/intervention and a commercial agent in combination must be 
reported as defined by the general guidelines provided by sponsors, 
Groups, Cancer Centers, or Principal Investigators. See Section 10.6. 
 
Expedited Reporting 
 
• An AE that occurs on a combination study must be assessed in accordance with 
the guidelines for investigational agents/interventions in Section 10.4, and where 
indicated, an expedited report must be submitted. 
 
• An AE that occurs prior to administration of the investigational 
agent/intervention must be assessed as specified in the protocol. In general, 
only Grade 4 and 5 AEs that are unexpected with at least possible 
attribution to the commercial agent require an expedited report.  Refer to 
Section 10.4 for specific AE reporting requirements or exceptions. 
 
• Commercial agent expedited reports must be submitted to the FDA via 
MedWatch 3500A. 
 
• An investigational agent/intervention might exacerbate the expected AEs 
associated with a commercial agent.  Therefore, if an expected AE (for the 
commercial agent) occurs with a higher degree of severity, expedited reporting 
is required.  The clinical investigator must determine severity. 
 
10.4          Expedited Reporting Requirements for IND/IDE Agents 
 
Expedited Reporting Requirements for Adverse Events that Occur on Studies under an 
IND/IDE within 30 Days of the Last Administration of the Investigational 
Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
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serious AEs, the investigator must determine both the intensity of the event and the 
relationship of the event to study drug administration.  
 
AEs which are serious must be reported to Takeda Pharmacovigilance (or designee) from 
the first dose of study drug through 30 days after administration of the last dose 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 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 
Pharmacovigilance (or designee). 
 
 
 
 
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, Shaji Kumar, MD, 
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. 
 
 
Regardless of expectedness or causality, all SAEs (including serious pretreatment events) 
must also be reported in English to Takeda Pharmacovigilance (or designee): 
 
 
Fatal and Life Threatening SAEs within 24 hours of the sponsor-investigator’s 
observation or awareness of the event 
 
 
All other serious (non-fatal/non-life-threatening) events within 4 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 
Pharmacovigilance. 
 
 
The sponsor-investigator must fax or email the 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. 
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• 
FAX: 1-800-881-6092 
• 
Hours: Mon-Fri, 9 a.m. – 7 p.m. ET 
 
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 Pharmacovigilance 
 
10.41 Special Situations for Expedited Reporting  
 
Exceptions to Expedited Reporting: EXPECTED Serious Adverse Events1 
 
An expedited report may not be required for specific Grade 1, 2, 3 and 4 Serious Adverse 
Events. Any protocol specific reporting procedures MUST BE SPECIFIED BELOW and 
will supercede the standard Expedited Adverse Event Reporting Requirements (see 
footnote 1):  
 
  
 
System Organ Class 
(SOC) 
 
Adverse event/ 
Symptoms 
 
CTCAE Grade at 
which the event 
will not be 
expeditedly 
reported. 
General disorders and 
administrations site 
conditions 
Fatigue  
≤ Grade 3 
 
 
Gastrointestinal 
Vomiting 
≤ Grade 3 
Nausea 
≤ Grade 3 
Diarrhea 
≤ Grade 3 
Investigations 
Neutrophil count 
decreased 
≤ Grade 4 
Platelet count 
decreased 
≤ Grade 4 
Lymphocyte count 
decreased 
≤ Grade 4 
White blood cell 
decreased 
≤ Grade 4 
Blood and lymphatic 
system disorders 
Anemia 
≤ Grade 4 
1  These exceptions only apply if the adverse event does not result in hospitalization.  If 
the adverse event results in hospitalization, then the standard expedited adverse events 
reporting requirements must be followed. 
 
Specific protocol exceptions to expedited reporting should be reported expeditiously by 
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10.5 
Other Required Reporting 
 
10.51 Persistent or Significant Disabilities/Incapacities 
 
Any AE that results in persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions (formerly referred to as 
disabilities), congenital abnormities or birth defects, must be reported 
immediately if they occur at any time following treatment with an agent under an 
IND/IDE since they are considered to be a serious AE and must be reported to 
the sponsor as specified in 21 CFR 312.64(b). 
10.52 Death 
Any death occurring within 30 days of the last dose, regardless of attribution to 
an agent/intervention under an IND/IDE requires expedited reporting within 24-
hours. 
 
Any death occurring greater than 30 days with an attribution of possible, 
probable, or definite to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
 
Reportable categories of Death  
 
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal:  A disorder characterized by cessation of life during the 
first 28 days of life.Death NOS:  A cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
• 
Sudden death NOS:  A sudden (defined as instant or within one hour of 
the onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
• 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benigh, malignant and unspecified (incl cysts and 
polyps) – Other (Progressive Disease)” under the system organ class 
(SOC) of the same name.  Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting tumor growth 
or progression: clinical deterioration associated with a disease process) 
should be submitted. 
• 
Any death occurring within 30 days of the last dose, regardless of 
attribution to the investigational agent/intervention requires expedited 
reporting within 24 hours. 
• 
Any death occurring greater than 30 days after the last does of the 
investigational agent/intervention requires expedited reporting within 24 


 
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hours only if it is possibly, probably, or definitely related to the 
investigational agent/intervention. 
 
10.53 Secondary Malignancy 
 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation or 
chemotherapy).  A secondary malignancy is not considered a metastasis of the 
initial neoplasm. 
 
• 
All secondary malignancies that occur following treatment with an agent under 
an IND/IDE be reported. Three options are available to describe the event: 
 
o 
Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic 
Leukemia [AML]) 
 
o 
Myelodysplastic syndrome (MDS) 
 
o 
Treatment-related secondary malignancy 
 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
 
10.54 Second Malignancy 
 
• 
A second malignancy is one unrelated to the treatment of a prior malignancy (and 
is NOT a metastasis from the initial malignancy).  Second malignancies require 
ONLY routine reporting. 
 
10.55 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, she must inform the investigator immediately and permanently 
discontinue study drug.  The sponsor-investigator must fax a completed 
Pregnancy Form to the 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 Millennium Department of Pharmacovigilance 
or designee (see Section 8.2).  Every effort should be made to follow the 
pregnancy for the final pregnancy outcome. 


 
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Suggested Pregnancy Reporting Form: 
Mayo Clinic Cancer Center (MCCC) Institutions:  Provide copies, along with the 
UPIRTSO cover sheet, by fax 
 to the MCCC Regulatory Affairs 
Unit (RAU) Risk Information Specialist who will determine and complete IRB 
reporting. The RAU will submit to the MCCC SAE Coordinator and the MCCC 
IND Coordinator to determine if FDA submission is needed. 
 
The Mayo SAE coordinator and/or Regulatory Affairs Until will notifiy Takeda 
at the address below (if applicable):  
 
SAE and Pregnancy Reporting Contact Information 
 
US & Canada 
Fax Number: 
 
Email
 
 
Rest of World 
 
Fax #:
 
 
 
10.6 
Required Routine Reporting 
 
Adverse events to be graded at each evaluation and pretreatment symptoms/conditions to 
be evaluated at baseline per the CTCAE v4.0 grading unless otherwise stated in the table 
below: 
 
 
SYSTEM ORGAN 
CLASS 
 
Adverse event/Symptoms 
 
Baseline 
Each 
evaluation 
Investigations 
Creatinine increased 
X 
X 
Neutrophil count decreased 
X 
X 
Platelet count decreased 
X 
X 
General disorders and 
administration site 
conditions 
 
Fatigue  
 
X 
 
X 
Gastrointestinal 
Disorders 
Nausea 
X 
X 
Vomiting 
X 
X 
Baseline # of Stools 
X 
 
Diarrhea 
 
X 
Constipation 
 
X 


 
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Infections and 
infestations 
Sepsis 
X 
X 
Blood and lymphatic 
system disorders 
Febrile neutropenia 
X 
X 
Skin and 
subcutaneous tissue 
disorders 
Rash, maculopapular 
X 
X 
Nervous system 
disorders 
 
Peripheral sensory neuropathy  
X 
X 
Peripheral motor neuropathy  
X 
X 
 
10.61 Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in Section 10.5: 
 
10.611 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
 
10.612 Grade 3 and 4 AEs regardless of attribution to the study treatment or procedure. 
 
 
10.613 Grade 5 AEs (Deaths) 
 
10.6131  
Any death within 30 days of the patient’s last study treatment or 
procedure regardless of attribution to the study treatment or 
procedure. 
 
10.6132 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, with a 
CTCAE type and attribution assigned. 
 
10.62 The MCCC Routine AE Data Submission Policy does not apply, as this study does not 
collect AE attribution.  Submit Grade 2 or greater AEs via the Nadir/AE Log when AEs 
experienced by the patient are not specified in Section 10.5. 
 
10.63    Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion of the 
Active Monitoring Phase (i.e., compliance with Test Schedule in Section 4.0). 
 
10.64 Distribution of Millennium Safety Updates 
 
Millennium Pharmaceuticals will send to the sponsor-investigator Ixazomib safety letters 
(real-time safety letters and/or the quarterly safety updates). All safety letters pertaining 
to the Ixazomib program will be sent to the Investigator-Sponsor via an electronic 
distribution using Mercury, the Millennium Secure File Transfer (MFT) system. For each 


 
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safety letter distributed, Sponsor-Investigator will receive an e-mail inviting to download 
the Adobe/PDF document from Mercury.    
 
10.65 To meet GCP requirements, Millennium is required to send Sponsor-Investigators the 
safety letters within 15 days after the world-wide receipt date of the safety event.  
Sponsor-Investigators responsibility is to read the safety letter, and provide the safety 
letter to the Institutional Review Board or Ethics Committee per institution’s policy. 
Sponsor-investigator will be responsible for forwarding such reports to any sub-
investigator(s).  
 
11.0 
Treatment Evaluation 
Cohort A (Multiple Myleoma): The International Myeloma Working Group (IMWG) uniform 
response criteria (Rajkumar et al, 2011) will be used to assess response to therapy  
11.1  
Terms and definitions 
 
• 
M-protein: synonyms include M-spike, monoclonal protein and myeloma protein, 
paraprotein, M-component. 
 
Serum M-protein level is quantitated using densitometry on SPEP except in cases 
where the SPEP is felt to be unreliable.   
• M-proteins migrating in the β-region (usually IgA M-proteins)  
• Cases in which the M-protein is so large and narrow on agarose (some 
specimens >4 g/dL) that they underestimate the actual immunoglobulin level 
(by greater than 1500 mg/dL) due to technical staining properties of the 
agarose gel. 
• Cases in which there are multiple peaks of same M-protein (aggregates or 
dimers) 
 
If SPEP is not available or felt to be unreliable (above examples) for routine M-
protein quantitation, then quantitative immunoglobulin levels derived from 
nephelometry or turbidometry can be accepted.  However, this must be explicitly 
reported at baseline, and only nephelometry can be used for that patient to assess 
response. SPEP derived M-protein values and quantitative nephelometric 
immunoglobulin values cannot be used interchangeably.   
 
Urine M-protein measurement is estimated using 24-h UPEP only.  Random or 24 h 
urine tests measuring kappa and lambda light chain levels are not reliable and are not 
recommended. 
 
 
FLC estimation is currently carried out using the serum FLC assay (Freelite, The 
Binding Site Limited, UK).  Patients with kappa/lambda FLC ratio <0.26 are defined 
as having monoclonal lambda FLC and those with ratios >1.65 as having a 


 
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monoclonal kappa FLC.  The monoclonal light chain isotype is considered the 
involved FLC isotype, and the opposite light chain type as the uninvolved FLC type.  
 
• 
Response terms: The following response terms will be used: stringent Complete 
Response (sCR), complete response (CR), very good partial response (VGPR), partial 
response (PR), Minimal Response (MR), stable disease (SD), and progressive disease 
(PD).  
 
In addition, for each response category, there will be an “unconfirmed” response 
category, which will be for internal use, for the purpose of guiding decision making 
and test ordering. These designations will applied at the time of the first measurement 
at which the quantitative aspect of the response category has been satisfied without 
the confirmation step having been satisfied. The designation “u” will precede the 
standard abbreviations, and will include usCR, uCR, uVGPR, uPR, uMR, uPD.  
 
• 
Measurable disease: Patients who have a measurable serum or urine M-protein.  
 
o Serum M-protein ≥1 g/dl  
o Urine M-protein ≥ 200 mg/24 h 
o Serum FLC assay: Involved FLC level ≥  10 mg/dl provided serum FLC ratio is 
abnormal 
o Bone marrow plasma cells ≥ 30% 
 
The serum free light chain (FLC) assay is of particular use in monitoring response to 
therapy in patients who have oligo-secretory or non-secretory disease and should be used 
in assessing response only if the baseline serum and/or urine M proteins are not 
“measurable” as above, and the baseline level of the involved FLC is “measurable.”  
When using this assay, it is important to note that the FLC levels vary considerably with 
changes in renal function and in patients with renal insufficiency, the levels of both the 
kappa and lambda may remain elevated, but the ratio normalizes with achievement of 
CR.  Thus, both the level of the involved and the uninvolved FLC isotype (i.e., the 
involved/uninvolved ratio or involved-uninvolved difference) should be considered in 
assessing response.  Patients included on the study on the basis of FLC alone (i.e., no 
measurable serum/urine M-protein) should be the only ones who are evaluated using 
FLC response criteria.  The others should follow usual criteria and ignore FLC results 
with the exception of defining stringent complete response. 
 
• 
Evaluable disease: Patients who do not have a “measurable” serum M-protein, 
serum free light chain, or urine M-protein. 
 
• 
Oligosecretory myeloma: Patient with multiple myeloma who has NEVER had 
“measurable” serum M-protein or urine M-protein, but has had a detectable M-
protein in his/her serum and/or urine and/or measurable serum free light chain.  
 


 
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• 
Non-secretory myeloma: Patient with multiple myeloma who has NEVER had a 
detectable M-protein in his/her serum and/or urine. 
 
11.2  
Clarification of test indications 
 
Listed below are the minimal required tests required to assess response based on the 
characteristics of their disease at on study.   
 
Table 11.2 
Tests  Required To Assess Response (Must Be Done At Each Disease Measurement Visit 
except as indicated1,2) 
On Study Baseline Value 
SPEP4  
24 hr 
UPEP2  
Ig 
FLC 
BM Bx 
Serum M-protein ≥1 g/dl, and urine M-protein≥ 
200 mg/24 hrs 
X 
X 
 
 
Serum M-protein ≥ 1 g/dl, but urine M-protein < 
200 mg/24 hrs 
X 
 
 
 
Serum M-protein <1 g/dl, and urine M-protein≥ 
200 mg/24 hrs 
 
X 
 
 
Serum M-protein < 1 g/dl, urine M-protein < 200 
mg/24 hrs, but involved Ig FLC is ≥10 mg/dL 
 
 
X 
 
Serum M-protein < 1 g/dl, urine M-protein< 200 
mg/24 hrs, involved Ig FLC is <10 mg/dL, bone 
marrow ≥30% plasma cells 
 
 
 
X3 
1  SPEP, UPEP, Immunofixation studies of both serum and urine, and Bone marrow 
biopsy are required to document CR regardless of registration values, and in addition 
FLC measurement and bone marrow immunophenotyping is required to document 
sCR.  SPEP and UPEP are required to document VGPR regardless of registration 
values. 
2  For serum measurable patients, 24 hour urine does not need to be confirmed (i.e. 
repeated after documented response) for any response category 
3  At a minimum, a bone marrow biopsy should be repeated every 3 months until 
documented response.  Bone marrow biopsy results do not need to be repeated after 
documented response. 
4    If serum M-protein is being followed by quantitative immunoglobulin levels derived 
from nephelometry or turbidometry, quantitative immunoglobulins are required.  SPEP 
is only required to document CR or VGPR.  
 
11.3 
Confirmed response  
 
In order to be classified as a hematologic response, confirmation of serum M- protein, 
serum immunoglobulin free light chain (when primary determinant of response) and 
urine M- protein (when primary determinant of response) results must be made by 
verification on two consecutive determinations.   


 
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• 
Bone marrow aspirate and biopsy are only required to document CR or sCR, 
except for patients with evaluable disease only, where a bone marrow is required 
to document all response categories including progression. However, a second 
confirmatory bone marrow is not required to confirm response in any case. 
• 
Radiographic studies are not required to satisfy these response requirements; 
however, if radiographic studies were performed there should be no evidence of 
progressive or new bone lesions. 
 
Appropriate tests required to document and confirm response are listed in Table 11.2 
 
11.4 
Bone progression  
 
Caution must be exercised to avoid rating progression on the basis of variation of 
radiologic technique alone.  Compression fracture does not exclude continued response 
and may not indicate progression.  When progression is based on skeletal disease alone, it 
should be discussed with the Study Chair before removing the patient from the study.  
 
 11.5 
 Response and Progression 
 
Criteria for response and progression are listed in Table 11.5. Progressive disease for all 
patients as defined in Table 11.5.  
 
 
Table 11.5 
CATEGORY 
RESPONSE CATEGORY a 
Stringent Complete 
Response (sCR) b 
• CR as defined plus 
• Normal FLC ratio and 
• Absence of clonal PCs by immunohistochemistry or 2- to 4- color 
flow cytometry i 
Complete Response 
(CR) b 
• Negative immunofixation of serum and urine c and 
• Disappearance of any soft tissue plasmacytoma and 
• <5% PCs in Bone Marrow and 
• If the only measurable disease is FLC, a normal FLC ratio d  
Very Good Partial 
Response (VGPR)  
• Serum and urine M-protein detectable by immunofixation but not 
on electrophoresis c or 
• ≥90% reduction in serum M-protein and urine M-protein <100 
mg/24 h c 
• If the only measurable disease is FLC, a >90% reduction in the 
difference between involved and uninvolved FLC levels 
Partial Response (PR) 
• If present at baseline, ≥ 50% reduction of serum M-protein and 
reduction in 24-hour urinary M-protein by ≥90% or to <200 
mg/24hrs c 
• If the only measurable disease is FLC, a ≥50% reduction in the 
difference between involved and uninvolved FLC levels 


 
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• If the only measurable disease is BM, a ≥ 50% reduction in BM 
PCs (provided the baseline PCs was ≥ 30%) 
• If present at baseline, ≥ 50% reduction in the size of soft tissue 
plasmacytomas 
Minor Response (MR)  
• If present at baseline, ≥25% but ≤ 49% reduction of serum M 
protein and reduction in 24-hour urine M-protein by 50-89% 
which still exceeds 200mg/24 hours c and 
• If present at baseline, 25-49% reduction in the size of soft tissue 
plasmacytoma and 
• No increase in the size or number of lytic bone lesions 
(development of compression fracture does not exclude response) 
Progressive Disease 
(PD) b, h 
 
Increase of 25% from lowest value in any of the following f, g: 
• Serum M-protein (absolute increase must be ≥ 0.5 g/dL) and/or 
• Urine M-protein (absolute increase must be ≥ 200 mg/24 hrs) 
and/or 
• If the only measurable disease is FLC, the difference between 
involved and uninvolved FLC levels (absolute increase must be 
>10 mg/dL)  and/or 
• If the only measurable disease is BM, bone marrow PC percentage 
(absolute increase must be ≥ 10%) e  
 
Or any one or more of the following: 
• Development of new bone lesion or soft tissue plasmacytoma or 
definite increase in the size of existing bone lesions or soft tissue 
plasmacytoma 
• Development of hypercalcemia (corrected serum calcium > 
11.5mg/dL) that can be attributed solely to the PC proliferative 
disorder 
Stable Disease (SD) 
Not meeting criteria for sCR, CR, VGPR, PR, MR or PD 
 
a All response categories require two consecutive assessments (sCR, CR, VGPR, PR, MR, PD) made at any time 
before the institution of any new therapy; sCR, CR, VGPR, PR, MR and SD 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. Bone marrow assessments need not be confirmed. Each category, 
except for stable disease, will have a working subcategory of “unconfirmed” [prefix ‘u”] to designate first time point 
at which response category MAY have been achieved if confirmed. 
 
b CR patient will need to progress at the same level as VGPR and PR patients to be considered a PD.  A positive 
immunofixation alone is not sufficient. 
 
c If more than one M protein spike meets the criteria for measurable disease at baseline, then both need to be 
followed for response.  Otherwise, only follow the measurable M protein spike for response.   
 
d In patients in whom the only measurable disease is by serum FLC levels: CR in such patients indicates a normal 
FLC ratio of 0.26-1.65 in addition to the CR criteria listed above. 
 


 
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e Bone marrow criteria for PD are only to be used in patients without measurable disease by M protein and by FLC;  
 
f A "25% increase" refers to M protein, FLC and bone marrow results and does not refer to bone lesions, soft tissue 
plasmacytoma or hypercalcemia.  The lowest value does not need to be a confirmed value.  If the lowest serum M-
protein is ≥ 5 g/dL, an increase in serum M-protein of ≥ 1 g/dL is sufficient to define disease progression. 
 
g In the case where a value is felt to be a spurious result per physician discretion (for example, a possible lab error), 
that value will not be considered when determining the lowest value. 
 
h Progressive disease should be confirmed.  However, treatment may be discontinued for progressive disease that is 
unconfirmed per physician discretion.  In this case, an objective status of PD should be entered on the measurement 
form and progressive disease should be reported on the event monitoring form. 
 
i Presence/absence of clonal cells is based upon the k/l ratio. An abnormal k/l ratio by immunohistochemistry 
requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is 
k/l of 4:1 or 1:2.  
Cohort B (light chain amyloidosis)   – The Amyloidosis Consensus Criteria response criteria will be 
used to assess response to therapy 
 
11.6 
Hematologic Response Considerations  
11.61 M-protein: synonyms include M-spike, monoclonal protein and myeloma 
protein, monoclonal paraprotein, M-component. 
 
Serum M-protein level is quantitated using densitometry on SPEP except in cases 
where the SPEP is felt to be unreliable.   
• M-proteins migrating in the β-region (usually IgA M-proteins)  
• Cases in which the M-spike is so large and narrow on agarose (some 
specimens >4 g/dL) that they underestimate the actual immunoglobulin 
level (by greater than 1500 mg/dL) due to technical staining properties of 
the agarose gel. 
 
If SPEP is not available or felt to be unreliable (above examples) for routine M-
protein quantitation, then quantitative immunoglobulin levels derived from 
nephelometry or turbidometry can be accepted.  However, this must be explicitly 
reported at baseline, and only nephelometry can be used for that patient to assess 
response. SPEP derived M-spike values and quantitative nephelometric 
immunoglobulin values cannot be used interchangeably.   
 
Urine M-protein measurement is estimated using 24-h UPEP only.  Random or 
24 h urine tests measuring kappa and lambda light chain levels are not reliable 


 
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and are not recommended. 
 
FLC estimation is currently carried out using the serum FLC assay (Freelite, The 
Binding Site Limited, UK).  Patients with kappa/lambda FLC ratio <0.26 are 
defined as having monoclonal lambda FLC and those with ratios >1.65 as having 
a monoclonal kappa FLC.  The monoclonal light chain isotype is considered the 
involved FLC isotype, and the opposite light chain type as the uninvolved FLC 
type. 
 
11.62 Response terms: The following response terms will be used: stringent Complete 
Response (sCR), amyloid complete response (ACR), very good partial response 
(VGPR), partial response (PR), minimal response (MR), stable disease or no 
response (SD), and progression or relapse (PD) and relapse from CR (RFCR). 
See Tables for definitions. 
 
In addition, for each response category, there will be an “unconfirmed” response 
category, which will be for internal use, for the purpose of guiding decision 
making and test ordering. These designations will applied at the time of the first 
measurement at which the quantitative aspect of the response category has been 
satisfied without the confirmation step having been satisfied. The designation “u” 
will precede the standard abbreviations, and will include usCR, uACR, uVGPR, 
uPR, uMR, uPD. 
 
11.63 Measurable disease: Patients who have a measurable serum or urine monoclonal 
protein by any of these means.  
• 
serum M-protein is ≥ 1 g/dL  
• 
urine M-spike is ≥ 200 mg/24 hours  
• 
  dFLC 5 mg/dL provided the kappa to lambda free light chain ratio 
is abnormal (primary criteria for response) 
 
The serum free light chain (FLC) assay is the most important parameter of 
response assessment. When using this assay, it is important to note that the FLC 
levels vary considerably with changes in renal function and in patients with renal 
insufficiency, the levels of both the kappa and lambda may remain elevated, but 
the ratio normalizes with achievement of CR. Thus both the level of the involved 
and the uninvolved FLC isotype (i.e., the involved/uninvolved ratio or involved-
uninvolved difference) should be considered in assessing response.  
 


 
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11.64 Confirmed response:  
 
11.641  
Confirmed hematologic response. In order to be classified as a 
confirmed hematologic response, confirmation of serum 
monoclonal protein, serum immunoglobulin free light chain 
(when primary determinant of response) and urine monoclonal 
protein (when primary determinant of response) results must be 
made by verification on two consecutive determinations.  Listed 
below are the minimal required tests required to assess response 
and confirm hematologic response based on the characteristics of 
their disease at on study.   
 
 
 Table 11.641 
Tests Required To Assess Response (Must Be Done At Each Disease 
Measurement Visit except as indicated1,2) 
On Study Baseline Value 
SPEP  
24 hr 
UPEP2,3  
Ig 
FLC 
BM 
Bx1,4 
Serum M-spike ≥1 g/dl, and urine 
M-spike≥ 200 mg/24 hrs, and 
involved serum FLC  ≥ 7.5 mg/dL  
X 
X 
X 
 
Serum M-spike ≥ 1 g/dl, but urine 
M-spike < 200 mg/24 hrs and 
involved serum FLC  ≥ 7.5 mg/dL 
X 
X 
X 
 
Serum M-spike<1 g/dl, and urine M-
spike≥ 200 mg/24 hrs and involved 
serum FLC  ≥ 7.5 mg/dL 
 
X 
X 
 
Serum M-spike < 1 g/dl, urine M-
spike < 200 mg/24 hrs, but and 
involved serum FLC  ≥ 7.5 mg/dL 
 
 
X 
 
Serum M-spike < 1 g/dl, urine M-
spike < 200 mg/24 hrs, involved 
serum FLC is <7.5 mg/dL, bone 
marrow ≥30% plasma cells 
 
 
 
X4 


 
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1  Bone marrow biopsy and immunofixation studies of both serum and urine 
are required to document ACR regardless of registration values, and in addition 
FLC measurement and bone marrow immunophenotyping is required to 
document sCR. Bone marrow biopsy results do not need to be confirmed (i.e. 
repeated after documented response) 
2  For serum measurable patients, 24 hour urine does not need to be confirmed 
(i.e. repeated after documented response) for any response category unless they 
have renal amyloid. In this group, the 24 hour urine is required to document 
organ response as well. 
3  For those patients with renal amyloidosis, the 24 hour urine protein 
electrophoresis should be done at every measurement 
4 For all disease categories, bone marrow biopsy is required to document sCR 
and ACR, but not PR, MR, or progression unless unmeasurable disease. 
 
11.642 
Confirmed organ response. In order to be classified as a 
confirmed organ response, the repeat testing listed in Table                 
11.642 is required. For organ progression, 2 observations beyond 
first suspected progression are allowed due to variability of 
results (see table below).  
Table 11.642 
  
Organ response 
Response test 
Confirmation required? 
Cardiac 
• 
NT-ProBNP 
• 
cTnT 
• 
NYHA stage 
 
Yes 
 
Yes 
 
Yes 
Renal 
• 
Creatinine 
• 
24 hour urine protein 
• 
 Creatinine clearance 
(optional) 
Yes 
 
Yes  
 
Optional 
 
Hepatic 
• 
Alkaline phosphatase 
• 
Liver image 
Yes 
 
Yes 
Neuropathy 
• 
Nerve conduction 
studies 
• 
Neurologic 
impairment score 
Yes 
 
 
 
Yes 


 
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11.643 Response and Progression: Criteria for hematologic response and 
progression are listed in Table 11.643 and for organ response in Table 
11.644.  
Table 11.643 
CATEGORY 
RESPONSE CRITERIAa 
Stringent complete 
response (sCR)   
• 
ACR as defined below plus all of the following 
• 
Absence of clonal cells in bone marrow by immunohistochemistry or 
immunofluorescenceb 
Amyloid Complete 
response (ACR). 
For the purpose of 
response assessment 
this is hematologic 
complete remission. 
• 
Negative immunofixation of the serum and urine  
• 
<5% plasma cells in bone marrow  
• 
Normal serum FLC ratio  
• 
If at on study, the only measurable non-bone marrow parameter was  
FLC, normalization of FLC ratio 
Very good partial 
response (VGPR) 
• 
dFLC (difference between the involved and uninvolved serum free light 
chain) <4 mg/dL 
Partial Response 
(PR) 
• 
dFLC >50% decrease 
No Response (NR) 
• 
≥25% but < 49% reduction of serum M-protein and reduction in 24h urine 
M-protein by 50-89%, which still exceeds 200 mg per 24 h 
Progressive disease 
(PD) 
Any one or more of the following:  
• 
Increase of 25% from lowest confirmed response in: 
 Serum M-component (absolute increase must be ≥0.5 g/dl)c 
 Serum M-component increase ≥1 g/dl, if lowest M component was 
≥5 g/dl 
 Urine M-component (absolute increase must be ≥ 200 mg/24 h)c  
 If at on study, the only measurable non-bone marrow parameter was 
FLC, the difference between involved and uninvolved FLC levels 
(absolute increase must be >10 mg/dl) 
 Bone marrow plasma cell percentage (absolute % must be ≥10%)c 
a All response categories require two consecutive assessments made at any time before the institution of any 
new therapy. 
b Presence/absence of clonal cells is based upon the k/λ ratio. An abnormal k/λ 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 k/λ  of >4:1 or <1:2.  


 
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c Positive immunofixation alone in a patient previously classified as ACR will not be considered 
progression. 
 
 
 


 
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Table 11.644 
ORGAN 
CRITERIA 
 
Response 
Progression 
Heart 
• 
NT-
ProBNP 
response 
 
 
• 
cTnT  
 
 
• 
EF  
 
>30% and >300 ng/L decrease 
if baseline NT-proBNP ≥ 650 
ng/L 
 
 
Only for progression 
 
 
Only for progression 
 
>30% and >300 ng/L increase 
 
 
 
 
≥ 33% increase 
 
 
≥ 10% decrease 
Renal 
 
50% reduction in 24-hour urine 
protein excretion (at least 0.5 
g/day). Creatinine and 
creatinine clearance must not 
worsen by 25% (minimum 
change of creatinine 0.5 mg/dL 
and of creatinine clearance 15 
ml/min).  
50% increase in urinary protein 
loss (at least 1 g/24 hours), or  
 
25% worsening of creatinine or 
creatinine clearance, (minimum 
change of 0.5 mg/dL and 15 
ml/min, respectively).  
Liver (any of 
following):  
 
Type A. ≥50% decrease in an 
initially elevated alkaline 
phosphatase level, or  
 
Type B. Decrease in liver size 
by at least 2 cm (radiographic 
determination).  
Type A. ≥50% increase of 
alkaline phosphatase above 
lowest level  
 
Type B. Increase in liver size 
by at least 2 cm (radiographic 
determination).  
Neuropathy (any 
of the following):  
Type A. Reduction in the 
Neuropathy Impairment Score 
(NIS) by 10 points. The NIS is 
based on the neurologic 
examination, and the items 
provide a measure of severity 
of muscle weakness (scored as 
0= normal, 1= 25%, 2= 50%, 
3= 75% weak, 4= paralyzed); 
loss of deep tendon reflexes 
scored as normal (0), decreased 
(1), or absent (2) and sensory 
loss graded as normal (0), 
diminished (1), or absent (2).  
 
Type B. Improvement in the 
Type A. Increase in the 
Neuropathy Impairment Score 
(NIS) by 10 points.  
 
Type B. Worsening in the 
summated compound muscle 
action potential (CMAP) 
amplitude by 2 mv. This value 
is derived from summated 
value of compound muscle 
action potential amplitudes of 
the tibial, peroneal and ulnar 
nerves from the nerve 
conduction studies. 
 


 
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ORGAN 
CRITERIA 
 
Response 
Progression 
summated compound muscle 
action potential (CMAP) 
amplitude by 2 mv. This value 
is derived from summated 
value of compound muscle 
action potential amplitudes of 
the tibial, peroneal and ulnar 
nerves from the nerve 
conduction studies.  
   
   
   
 
 
 
12.0 
Descriptive Factors  
 
12.1 
Cohort A only: Parameters followed for hematologic response (pick one):.serum 
monoclonal protein ≥ 1 g/dL and urine M-spike ≥200 mg/24 hours vs. serum monoclonal 
protein ≥1g/dL only vs. urine M-spike ≥200 mg/24 hours only vs. serum immunoglobulin 
free light chain ≥10 mg/dL. Distinguish between SPEP measurement versus quantitative 
IgA measurement for serum monoclonal protein.    
12.2 
Autologous stem cell transplant: eligible vs. not eligible 
12.3 
Dose level:  -2 vs. -1 vs. 0 vs. 1 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
 
13.1 
Patients who are sCR, CR, VGPR, PR, MR, or SD (or usCR, uCR, uVGPR, uPR, uMR) 
will continue treatment per protocol. 
 
13.2 
Patients who develop progressive disease or start alternate therapy while receiving 
therapy will go to the event-monitoring phase. 
 
13.3 
Patients who go off protocol treatment for reasons other than PD, including stem cell 
transplantation, will go to the event-monitoring phase per Section 18.0. 
 
13.4 
Patients who are discontinued from therapy for an unacceptable adverse event(s) will be 
followed until resolution or stabilization of the AE(s). 
    
13.5 
Criteria for Patient Withdrawal from Study Treatment 
 
Patients may be withdrawn from the study for the following reasons: 
 


 
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• 
Progressive multiple myeloma 
• 
Patient refuses further treatment on the trial 
• 
Patient develops an intercurrent illness that precludes further participation, or 
requires a prohibited concomitant treatment 
• 
The Investigator withdraws the patient in the patient’s best interests 
• 
Patient is lost to follow-up (defined as the inability to contact the patient on 3 
separate occasions) 
• 
Administrative reasons (e.g., the patient is transferred to hospice care) 
• 
An adverse event, which in the opinion of the Investigator, precludes further trial 
participation  
 
All attempts should be made to complete the End of Study procedures if a patient 
withdraws from the trial early. 
 
13.6 
Criteria for Study Discontinuation 
 
The study may be temporarily or permanently discontinued at any site and at any time.  
Reasons for study discontinuation may include, but are not limited to, the following: 
 
• 
Safety concerns 
• 
Poor enrollment 
• 
Non-compliance with the protocol, Good Clinical Practice guidances or other 
regulatory requirements by the Investigator(s) 
• 
Request to discontinue the trial by a regulatory or health authority or an IRB 
• 
Manufacturing difficulties/concerns 
 
All Investigators and the requisite regulatory authorities will be notified if the study is 
suspended or terminated for safety reasons.  In the case of such termination, the 
Investigator will notify the IRB. 
 
13.7 
Phase I only:  If a patient fails to complete the first cycle of treatment for reasons other 
than toxicity, the patient will be regarded as inevaluable and will be replaced.    
 
13.8 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry.  
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable).  
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted.  Event monitoring will be required per Section 18.0 
of the protocol.  
• 
If the patient never received treatment, on-study material and the End of Active 
Treatment/Cancel Notification Form must be submitted.  No further data submission 
is necessary. 


 
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13.9a 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable.  All data up until the point of confirmation of a major violation must be 
submitted.  The patient will go directly to the event-monitoring phase of the study.  The 
patient may continue treatment off-protocol at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered.  Event monitoring 
will be required per Section 18.0 of the protocol. 
13.9b A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given.  On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted.  No further data submission is necessary. 


 
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14.0 
Body Fluid Biospecimens: Cohort A ONLY  
 
14.1  
Summary Table of Research Blood and Body Fluid Specimens to be collected for this Protocol: Pharmacokinetic sampling is 
included in this study. The sampling schedule is as shown below. 
 
 
 
Correlative Study 
(Section for more 
information) 
Mandatory 
or 
Optional 
Blood or 
Body Fluid 
being 
Collected 
Type of 
Collection 
Tube 
(color of 
tube top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
Cycle 1 
Cycle 
2 
Process 
at site? 
(Yes or 
No) 
Temperature 
 Conditions 
for Storage 
/Shipping  
Day 1 
(post-
dose, 
hours 1 & 
4)  
Day8 
(pre-
dose) 
Day 
15 
(pre-
dose) 
Day 22 
Anytime 
Day 1 
(pre-
dose) 
 
 
Pharmacokinetics Mandatory 
Blood 
EDTA 
(lavender) 
4 mL 
(1) 
X 
X 
X 
X 
X 
Yes 
Store -70, ship 
on cry ice  
 
 
 


 
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14.2  
Collection and Processing:   
 
Collect 3ml of blood into chilled 4ml K2 EDTA tube (lavender top tube) per time point. 
Gently invert tube 8-10 times to mix the additive with the collection blood prior to 
centrifugation. Place immediately on wet ice. Centrifuge the container for 30 minutes at 
approximately 3000 rpm at approximately 4ºC in a refrigerated Centrifuge. Immediately 
following centrifugation, gently remove the plasma from the packed cells and aliquot into 
two transfer vials filled with lyophilized citric acid. Each aliquot should contain exactly 
0.500ml of plasma. Vortex split tubes well. Any remaining plasma can be discarded. 
Replace cap on tube and freeze the samples immediately at -70ºC. No more than 60 
minutes will elapse between blood collection and freezing the plasma samples. Keep 
samples frozen at -70ºC or lower until shipment  
 
Pharmacokinetic (PK) Sample Collection and Handling 
 
Blood samples for PK assessment must be collected in 3-mL Vacutainer tubes containing 
K2EDTA as the anticoagulant.  Resulting blood and plasma PK samples must be stored 
in plastic storage tubes with caps.  No blood collection tubes with separation gel should 
be used. 
All tubes must be labeled.  The printed information must include the study number, 
patient identification number, treatment period, and scheduled sampling day and time.  
No other information will be written on the labels. 
Preparation of Plasma Pharmacokinetic Samples 
1. Draw blood into labeled and chilled 3 mL lavender top K2EDTA Vacutainer tube.  
 
2.  Mix the blood with the anticoagulant by gently inverting the tube 8-10 times and 
immediately place on wet ice.   
 
3.  Centrifuge the blood samples for 10 minutes at 1006g at 4º C in a refrigerated 
centrifuge within 10 mins of sample collection  
 
4.  Immediately following centrifugation, gently remove the plasma from the packed 
cells and aliquot into two transfer vial filled with lyophilized citric acid. Each aliquot 
should contain 0.5 mL of plasma. 
 
5. Vortex split tubes thoroughly. Any remaining plasma post split1/split 2 sample 
aliquots should be discarded following appropriate biohazard disposal procedures. 
 
NOTE: If < 0.5 mL plasma is obtained post centrifugation, do not process or store split1 
or split2, record split1: ISV (Insufficient Sample Volume), split2: ISV. If < 1.0 mL 
plasma is obtained post centrifugation, process and store split1 according to procedure; 
do not process or store split2, record split 2: ISV. Discard remaining plasma using 
appropriate biohazard waste disposal procedures. 
 
6. Replace cap on tube and freeze the samples immediately at -70°C 
 


 
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Note:  No more than 60 minutes should elapse between blood collection and freezing the 
plasma samples. 
 
7. Keep samples frozen at -70°C or lower until shipment. 
 
Note:  Wet ice is defined as a mixture of ice and water 
Radius of 
rotation (rotor 
arm length) 
(cm) 
RPM speed needed to 
achieve 1000g 
4 
4743 
5 
4242 
6 
3873 
7 
3585 
8 
3354 
9 
3162 
10 
3000 
11 
2860 
12 
2738 
13 
2631 
14 
2535 
15 
2449 
 
Excel formula if rotor length not listed in above table: 
RPM = SQRT(( 1006/(0.00001118*rotor length in cm)) 
Questions regarding handling the plasma pharmacokinetic specimens should be addressed to the 
contact person designated by Millennium. 
 
.  
 
14.3 
Shipping and Handling 
Shipment of Pharmacokinetic Samples 
All pharmacokinetic samples must be sent to the bioanalytical laboratories specified 
below in a single shipment at the end of the study or in multiple shipments as agreed 
upon with the lab (Ixazomib PK samples currently have 618 days of stability and will 
need to be analyzed before reaching the end of their stability).  An inventory list must be 
included with each shipment.  The inventory list must note each specimen drawn for each 
patient, and note any missing specimens. 
 
The investigator must follow the instructions below: 
• 
For all international shipments, a courier will be designated. 


 
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• 
Notify the bioanalytical laboratories and the designated courier at least 24 hours in 
advance of the planned shipment.  Provide the designated courier with the 
appropriate account number to be used, if applicable. 
• 
Samples should be shipped via overnight delivery only on Monday through 
Wednesday, excluding holidays. 
• 
Double-bag the frozen samples for each patient in bags that can withstand dry ice 
conditions. 
• 
Pack the frozen samples in sufficient quantity of dry ice in appropriate containers, to 
maintain a frozen state for at least 3 days. 
• 
Avoid direct contact between sample bags and dry ice by separating them with a dry 
ice resistant material (eg, newspaper). 
• 
For all biological samples, follow the International Air Transport Association (IATA) 
regulations for shipment. 
• 
Ensure that the total package weight does not exceed 27.2 kg (60 pounds). 
• 
Label the package with the sponsor-investigator name and study number. 
• 
Include a return address (which includes the investigator’s name) on the outside of 
each shipping container. 
• 
Comply with all courier regulations for the shipment of biological specimens (include 
all paperwork). 
• 
Retain all documents indicating date, time, and signature(s) of person(s) making the 
shipment in the study files. 
As soon as shipment day and air bill number(s) are available, the site must call or fax the 
bioanalytical laboratories.  The call or fax must specify the study number, number of 
packages shipped, the number of pharmacokinetic samples, and the time of shipment 
pick-up. 
 
Ship the samples for each patient after the final C2D1 predose samples are obtained. Ship 
the samples on dry ice. 
 
Samples should be shipped to: 
Ship To: 




 
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Ixazomib that is dispensed to the patient for take-home dosing should remain in 
the blister packaging until the point of use. The investigative site is responsible 
for providing the medication to the patient in units that comprise the correct daily 
dose configurations.  Capsules should remain in the blisters until the point of use.  
Ixazomib capsules must be administered as intact capsules and must not be 
opened or manipulated in any way.  Comprehensive instructions should be 
provided to the patient in order to ensure compliance with dosing procedures.  
Patients will be instructed to store the medication in the refrigerator until the time 
of use. Reconciliation will occur accordingly when the patient returns for their 
next cycle of therapy. Any extremes in temperature should be reported as an 
excursion and will be managed on a case by case basis.  Returned unused 
capsules should be discarded in a proper biohazard container. 
 
Ixazomib is an anticancer drug. As with other potentially toxic compounds, 
caution should be exercised when handling Ixazomib.  It is recommended to wear 
gloves and protective garments during preparation when dispensed in clinic. 
Please refer to published guidelines regarding the proper handling and disposal of 
anticancer agents. 
 
15.14 Administration:  Ixazomib capsules must be administered as intact capsules and 
are not intended to be opened or manipulated in any way.  Capsules should be 
taken on an empty stomach with approximately 8 oz (1 cup) of water (no food for 
2 hours before and for 1 hour after dosing). 
 
 
Ixazomib should not be taken if the patient has had a serious allergic reaction to 
boron or boron containing products 
 
15.15 Pharmacokinetic information:  a) Absorption:  After oral dosing, ixazomib is 
rapidly absorbed with a median Tmax of 1 hour.  The lack of a discernible 
relationship between BSA and ixazomib clearance over a relatively wide BSA 
range (1.4-2.6 m2) indicates that total systemic exposure (AUC) following fixed 
dosing should be independent of the individual patient’s BSA.  A high-fat meal 
decreased both the rate and extent of absorption.  Therefore, ixazomib should be 
administered on an empty stomach.   
b) Distribution: The steady state volume of distribution is large and is estimated 
to be 543 L. Ixazomib is 88-94% protein bound. 
c) Metabolism:  Metabolism is the primary route for elimination of ixazomib by 
both CYP and non-CYP enzymes. CYP3A4 and 1A2 comprise the major CYP 
isozymes that contribute to ixazomib metabolism. 
d) Excretion: The mean terminal half-life is 9.5 days.  Renal elimination is a 
minor clearance pathway for ixazomib.  Dosing adjustment is not required in 
patients with mild and moderate renal impairment in studies. However, in a 
dedicated renal impairment study (C16015), unbound AUC0-last was 38% higher 
in patients with severe renal impairment or 
end-stage renal disease (ESRD) requiring dialysis as compared to patients with 
normal renal function.  Accordingly, a reduced starting dose of ixazomib is 
recommended in patients with severe renal impairment and ESRD requiring 
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with moderate or severe hepatic impairment as compared to patients with normal 
hepatic function.  A reduced starting dose of ixazomib is recommended for 
patients with moderate or severe hepatic impairment. 
 
    
 
15.16 Potential Drug Interactions:  The PK of Ixazomib was similar with and without 
coadministration of clarithromycin, a strong CYP3A inhibitor, and therefore no 
dose adjustment is necessary when Ixazomib is administered with CYP3A 
inhibitors. In the population PK analysis, coadministration of strong CYP1A2 
inhibitors did not affect Ixazomib clearance. Thus, no dose adjustment is required 
for patients receiving strong CYP1A2 inhibitors. In a clinical rifampin DDI 
study, Ixazomib Cmax and AUC0-last were reduced in the presence of rifampin 
by approximately 54% and 74%, respectively. As a result, the coadministration 
of strong CYP3A inducers with Ixazomib should be avoided.  Ixazomib is neither 
a time-dependent nor reversible inhibitor of CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 
2D6, or 3A4/5, therefore the potential for Ixazomib to produce DDIs via CYP 
isozyme inhibition is low.  Ixazomib did not induce CYP1A2, CYP2B6, and 
CYP3A4/5 activity.  The potential for Ixazomib to cause DDIs with substrates or 
inhibitors of P-gp, BCRP, MRP2, MATE-1, MATE2-K, OCT2, OAT1, OAT3, 
and OATPs is low. 
 
Pharmacokinetic parameters for Ixazomib coadministered with lenalidomide and 
dexamethasone (LenDex) are similar to those observed when Ixazomib is 
administered as a single agent. This suggests that there is no readily apparent 
effect of coadministration of LenDex on the clinical PK of Ixazomib. 
 
Ixazomib should not be taken if the patient has had a serious allergic reaction to 
boron or boron containing products. 
 
15.17 Known potential toxicities:  See the current version of the Investigator’s 
Brochure for more complete information including potential risks, as well as 
recommendations for clinical monitoring and medical management of toxicity. 
 
Very common (≥10%): anemia, neutropenia, thrombocytopenia, 
constipation, diarrhea, nausea, vomiting, fatigue,     decreased appetite, , 
peripheral neuropathy    
Common (≥1% to <10%): Herpes zoster,   peripheral sensory 
neuropathy, erythema, rash, erythematous rash, pruritic rash, macular rash, 
peripheral edema, upper respiratory tract infection, back pain, maculo-
papular rash, papular rash 
 
Uncommon (≥0.1% to <1%): generalized pruritis, generalized rash    
 
Herpes zoster – antiviral prophylaxis should be considered in patients 
being treated with Ixazomib to decrease the risk of herpes zoster 
reactivation. 
 


 
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Rare but serious risks – intestinal obstruction, pneumonia, life-
threatening severe skin rash (Steven Johnson syndrome, TEN, DRESS 
syndrome), thrombotic thrombocytopenic purpura, tumor lysis syndrome, 
renal failure, posterior reversible encephalopathy syndrome, transverse 
myelitis, progressive multifocal leukoencephalopathy. 
Overdose – There is no known specific antidote for Ixazomib overdose.  In 
the event of an overdose in blinded studies, study medication assignment 
should be unblinded immediately.  The clinician should consider admitting 
the patient to the hospital for IV hydration, monitoring for adverse drug 
reactions, monitoring of vital signs, and appropriate supportive care.  
Gavage may be considered, but it should be kept in mind that Ixazomib 
absorption is rapid.  Ixazomib is not readily dialyzable.   
  
15.18 Drug procurement and accountability:  Investigational product will be 
supplied free of charge to trial participants by Millennium Pharmaceuticals, Inc. 
 
 
15.19  Nursing Guidelines 
 
15.191 Capsules must be administered intact and should not be opened or 
manipulated in any way. Additionally, capsules should remain in the 
blister packs until they are ready to be taken. It is recommended to wear 
gloves and protective garments during preparation when dispensed in 
clinic. 
 
15.192 Capsules should be taken on an empty stomach (either 1 hour before or 2 
hours after meals) with 8 oz of water. 
 
15.193 Cytopenias have been observed. Monitor CBC w/diff.  Instruct patient to 
report any signs or symptoms of infection or bleeding to the study team. 
 
15.194 GI side effects have been seen (nausea, diarrhea, vomiting), treat 
symptomatically and monitor for effectiveness of intervention. 
 
15.195 Rash has been seen. Rarely Steven Johnson syndrome (SJS) has been 
seen with this agent. Instruct patients to report any rash to study team. 
 
15.196 Assess patients concomitant medications, including over the counter and 
supplements. Ixazomib is metabolized through both CYP and non-CYP 
enzymes, and drug to drug interactions exist. Instruct patients not to start 
any new medications or supplements without checking with the study 
team first. 
 
15.197 Fatigue has been seen.  Instruct patient in energy conserving lifestyle. 
 
15.198 Insomnia can be seen.  Treat symptomatically and monitor for 
effectiveness. 
 
15.199a Patients who have had an allergic reaction to boron or boron containing 
products should not take MLN9708. 


 
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15.199b The following rare but life threatening conditions have been seen with 
agent: CHF, liver failure, TTP, TLS, renal failure, bowel obstruction, and 
RPLS, transverse myelitis, progressive multifocal leukoencephalopathy.  
Monitor labs closely, instruct patient to report any new or worsening 
symptoms to the study team and provide further assessment based on 
symptoms. 
15.2 
Dexamethasone for Oral Administration (DXM) 
 
15.21 Background: Dexamethasone is an adrenal corticosteroid compound. 
Dexamethasone decreases inflammation by suppression of neutrophil migration, 
decreased production of inflammatory mediators, and reversal of increased 
capillary permeability; suppresses normal immune response. Dexamethasone’s 
mechanism of antiemetic activity is unknown. 
 
15.22 Formulation: Commercially available for oral administration as:  
 
Tablets [scored]: 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 4 mg, and 6 mg 
 
Solution, oral: 0.5 mg/mL (500 mL) 
Solution, oral concentrate: Dexamethasone Intensol: 1 mg/mL (30 mL) 
 
15.23 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions. Store oral tablets at room 
temperature between 20ºC to 25ºC (60ºF to 77ºF). Protect from moisture. 
Dispense in a well-closed, light-resistant container as defined in the 
USP/NF. Store oral liquid at room temperature, do not freeze. Do not use 
if solution contains a precipitate. Refer to commercial package for drug 
expiration date. 
 
15.24 Administration:  Refer to the treatment section for specific administration 
instructions. May be taken with meals to decrease GI upset.  
 
 
15.25 Pharmacokinetic information: 
Onset of action: Prompt 
Duration of metabolic effect: 72 hours 
Metabolism: Hepatic 
Half-life elimination: Normal renal function: 1.8-3.5 hours; Biological 
half-life: 36-54 hours 
Time to peak, serum: Oral: 1-2 hours 
Excretion: Urine and feces 
 
 
15.26 Potential Drug Interactions: 
Cytochrome P450 Effect: Substrate of CYP3A4 (major); Induces 
CYP2A6 (weak), 2B6 (weak), 2C8 (weak), 2C9 (weak), 3A4 (strong) 
Increased Effect/Toxicity: Aprepitant, azole antifungals, calcium channel 
blockers, cyclosporine, estrogens, and macrolides may increase the serum 
levels of corticosteroids. Corticosteroids may increase the hypokalemic 
effects of amphotericin B or potassium-wasting diuretics (loop or 
thiazide); monitor. Refer to the package insert for a listing of other drugs. 


 
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Decreased Effect: Antacids and bile acid sequestrants may reduce the 
absorption of corticosteroids; may reduce the absorption of corticosteroids; 
separate administration by 2 hours. Aminoglutethimide, barbiturates, and 
CYP3A4 inducers may reduce the serum levels/effects of dexamethasone 
and dexamethasone may decrease the levels/effects of other CYP3A4 
substrates. Serum concentrations of isoniazid may be decreased by 
corticosteroids. Corticosteroids may lead to a reduction in warfarin effect. 
Corticosteroids may suppress the response to vaccinations. 
Ethanol/Nutrition/Herb Interactions:  
Ethanol: Avoid ethanol (may enhance gastric mucosal irritation). 
Food: Dexamethasone interferes with calcium absorption. Limit caffeine. 
Herb/Nutraceutical: Avoid cat’s claw (Uncaria tomentosa), echinacea 
(have immunostimulant properties) 
 
15.27 Known potential adverse events: Consult the package insert for the most 
current and complete information.  
 
Common known potential toxicities, frequency not defined:   
Fluid and electrolyte disturbances, congestive heart failure in susceptible 
persons, hypertension, euphoria, personality changes, insomnia, 
exacerbation of infection, exacerbation or symptoms of diabetes, 
psychosis, muscle weakness, osteoporosis, vertebral compression 
fractures, pancreatitis, esophagitis, peptic ulcer, dermatologic disturbances, 
convulsions, vertigo and headache, endocrine abnormalities, ophthalmic 
changes, and metabolic changes. Some patients have experienced itching 
and other allergic, anaphylactic or hypersensitivity reactions. Withdrawal 
from prolonged therapy may result in symptoms including fever, myalgia 
and arthralgia. 
 
15.28 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
15.29 Nursing Guidelines: 
 
15.291 Monitor patient regularly for hypertension, CHF and other evidence of 
fluid retention. 
 
15.292 Advise patient of possible mood or behavioral changes, i.e., depression, 
euphoria, insomnia, even psychosis.  Instruct patient to report any 
suspected changes to healthcare team. 
 
15.293 Assess for symptoms of gastric ulcer, heartburn, or gastritis.  Suggest 
antacids.  Instruct patient to report symptoms to healthcare team if unable 
to control. 
 
15.294 Evaluate signs of infection, particularly local candidal infections and 
treat appropriately. 
 
15.295 Monitor blood glucose frequently. 
 


 
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15.296 Instruct patient to report frequent, unrelenting headaches or visual 
changes to healthcare team. 
 
15.297 Advise patient that easy bruising is a side effect. 
 
 
 
15.3 
Cyclophosphamide for Oral Administration (Cytoxan®, Neosar®, CTX) 
 
15.31 Background: Cyclophosphamide is an alkylating agent that prevents cell 
division by cross-linking DNA strands and decreasing DNA synthesis. It is a cell 
cycle phase nonspecific agent. Cyclophosphamide also possesses potent 
immunosuppressive activity. Cyclophosphamide is a prodrug that must be 
metabolized to active metabolites in the liver. 
 
15.32 Formulation: Commercially available for oral administration as:  
 
Tablets: 25 mg, 50 mg  
 
15.33 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions. Store oral tablets at room 
temperature preferably below 25ºC (77ºF). This product will withstand 
brief exposure to temperatures up to 30ºC (86ºF), but should be protected 
from temperatures above 30ºC (86ºF). Dispense in a tight container as 
defined in the USP/NF. Refer to labeling on the bottle for expiration date 
of the commercial tablets. 
  
15.34 Administration:  Refer to the treatment section for specific administration 
instructions. Tablets are not scored and should not be cut or crushed. To 
minimize the risk of bladder irritation, do not administer tablets at bedtime. 
 
 
15.35 Pharmacokinetic information: 
Distribution: Vd: 0.48-0.71 L/kg; crosses placenta; crosses into CSF (not 
in high enough concentrations to treat meningeal leukemia) 
Protein binding: 10% to 60% 
Bioavailability: >75% 
Time to peak, serum: Oral: ~1 hour 
Metabolism: Hepatic to active metabolites acrolein, 4-aldophosphamide, 
4-hydroperoxycyclophosphamide, and nor-nitrogen mustard 
Half-life elimination: 3-12 hours 
Excretion: Urine (<30% as unchanged drug, 85% to 90% as metabolites) 
 
 
15.36 Potential Drug Interactions: 
Cytochrome P450 Effect: Substrate of  CYP2A6 (minor), 2B6 (major), 
2C9 (minor), 2C19 (minor), 3A4 (major); Inhibits CYP3A4 (weak); 
Induces CYP2B6 (weak), 2C8 (weak), 2C9 (weak)  
Increased Effect/Toxicity: Allopurinol may cause an increase in bone 
marrow depression and may result in significant elevations of 
cyclophosphamide cytotoxic metabolites. CYP2B6 and CYP3A4 inducers 
may increase the levels/effects of acrolein (the active metabolite of 
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may enhance the adverse effects of cyclophosphamide. Cyclophosphamide 
reduces serum pseudocholinesterase concentrations and may prolong the 
neuromuscular blocking activity of succinylcholine and mivacurium. 
Decreased Effect: Cyclophosphamide may decrease the absorption of 
digoxin tablets. CYP2B6 and CYP3A4 inhibitors may decrease the 
levels/effects of acrolein (the active metabolite of cyclophosphamide); see 
package insert for example inhibitors. 
Herb/Nutraceutical Interactions: Avoid black cohosh, dong quai in 
estrogen-dependent tumors.  
 
15.37 Known potential adverse events: Consult the package insert for the most 
current and complete information.  
 
Common known potential toxicities, > 10%:   
Dermatologic: Alopecia but hair will usually regrow although it may be a 
different color and/or texture. Hair loss usually begins 3-6 weeks after the 
start of therapy. 
Endocrine & metabolic: Fertility: May cause sterility; interferes with 
oogenesis and spermatogenesis; may be irreversible in some patients; 
gonadal suppression (amenorrhea) 
Gastrointestinal: Nausea and vomiting, usually beginning 6-10 hours after 
administration; anorexia, diarrhea, mucositis, and stomatitis are also seen 
Hematologic: Thrombocytopenia and anemia are less common than 
leukopenia 
 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Facial flushing 
Central nervous system: Headache 
Dermatologic: Skin rash 
 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Cyclophosphamide may potentiate the cardiac toxicity of anthracyclines. 
Other adverse reactions include anaphylactic reactions, darkening of 
skin/fingernails, dizziness, hemorrhagic colitis, hemorrhagic ureteritis, 
hepatotoxicity, hyperuricemia, hypokalemia, jaundice, malaise, 
neutrophilic eccrine hidradenitis, radiation recall, renal tubular necrosis, 
secondary malignancy (e.g., bladder carcinoma), SAIDH, Stevens-Johnson 
syndrome, toxic epidermal necrolysis, weakness. 
 
15.38 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
 
15.39 Nursing Guidelines:  
 
 
 
 
15.391 Myelosuppression is common. Monitor CBC including platelets. Instruct 
patient on signs/symptoms of infection and to inform health care team of 
any unusual bruising, or signs of bleeding. 
 


 
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15.392 Instruct patient to drink 2-3 liters of fluid per day for 2-3 days following 
treatment and to void frequently, not greater than every three hours to 
facilitate keeping the bladder clear of drug. 
 
 
 
 
15.393 Instruct patient to report any urinary urgency, frequency, dysuria, or 
hematuria. Administer mesna with high dose cytoxan to prevent 
hemorrhagic cystitis.  It may be necessary to catheterize and provide 
constant bladder irrigation. 
 
 
 
 
15.394 Advise patient in possible strong metallic taste associated with Cytoxan 
and suggest hard candy with a strong flavor (cinnamon, peppermint) to 
alleviate it. 
 
 
 
 
15.395 Administer antiemetics as necessary to minimize nausea and vomiting, 
which usually occurs 6-8 hours after administration. 
 
 
 
 
 
15.396 Report and record any complaint of lightheadedness, facial “heat 
sensation,” diaphoresis during administration. 
 
 
 
 
15.397 Use of an ice cap may be helpful in preventing or limiting alopecia. 
 
 
 
 
15.398 Corticosteroids, phenothiazine, imipramine, vitamin A succinylcholine, 
digoxin, thiazide diuretics, warfarin and allopurinol may inhibit Cytoxan 
metabolism and modify its’ effect.  They may also increase bone marrow 
suppression. 
 
 
 
 
 
 
15.399a Advise female patients of possible menstrual changes or amenorrhea. 
 
 
 
 
15.399b Patients on anticoagulant therapy should have INR levels 
carefully monitored as cytoxan increases their effect. 
 
 
 
 
15.399c Monitor electrolytes and for signs/symptoms of SIADH and 
tumor lysis syndrome. 
 
 
 
 
15.399d Monitor digoxin levels closely as cytoxan may decrease these levels. 
 
 
 
 
15.399e Cytoxan may potentiate doxorubicin-induced cardiomyopathy. Instruct 
patient to report any chest pain. 
  
 
16.0  
Statistical Considerations and Methodology  
 
16.1 
Overview:  This is a phase I/II study of a novel regimen of Ixazomib with 
cyclophosphamide and dexamethasone for treatment in two cohorts of patients:   initial 
treatment of newly diagnosed multiple myeloma patients requiring therapy (cohort A) and 
treatment of light chain amyloidosis (cohort B).  The phase I study is designed to 
determine the maximally tolerated dose (MTD) and toxicity profile of Ixazomib in 
combination with cyclophosphamide and dexamethasone in patients with previously 


 
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untreated multiple myeloma using the standard cohort 3+3 design. The phase II portion is 
designed to assess the complete plus very good partial response rate associated with 
therapy with Ixazomib in combination with cyclophosphamide and dexamethasone, in 
patients with previously untreated multiple myeloma using a single stage phase II study 
design  (cohort A).  As of Addendum 9, a second single stage phase II study design is 
being added to assess the hematologic response rate of this regimen in patients with light 
chain amyloidosis (cohort B).    
 
16.11 
Endpoint: The primary endpoint of the phase I portion of this trial is to assess the 
maximum tolerated dose (MTD).  For cohort A of the phase II portion of this 
trial, the primary endpoint is the rate of complete or very good partial response.  
A success will be defined as a an sCR,a, CR or VGPR noted as the objective 
status on two consecutive evaluations. For cohort B of the phase II portion, the 
primary endpoint is the rate of hematologic response.   A success will be defined 
as an sCR, ACR, VGPR, or PR noted as the objective status on two consecutive 
evaluations.  Response will be evaluated using the first 12 cycles (induction 
therapy).  Throughout Section 16.0, sCR, CR, or VGPR (cohort A) or sCR, ACR, 
VGPR, or PR (cohort B) will be considered synonymous with “success” in the 
phase II portion, unless specified otherwise.    
 
16.12 
Sample Size:  The phase I portion of this study is expected to require a minimum 
of 6 and a maximum of 12 evaluable patients.  The 6 patients treated at the MTD 
in the phase I portion will also be included in the phase II portion.  A maximum 
of 35 additional evaluable patients will be accrued at the MTD dose level for a 
maximum of 41 evaluable patients in the phase II portion of this study. We 
anticipate accruing up to 4 additional patients (1 phase I, 3 phase II) to account 
for ineligibility, cancellation, major treatment violation, or other reasons. 
Therefore, a maximum of 13 patients will be accrued in the phase I portion and a 
maximum of 38 patients will be accrued to the phase II portion for an overall 
maximum of 51 patients for the entire study. 
 
As of Addendum 9, 51 patients have been accrued to cohort A and cohort B is 
being added to the phase II portion of this study.  A maximum of 33 evaluable 
patients will be accrued to cohort B.  We anticipate accruing up to 3 additional 
patients to account for ineligibility, cancellation, major treatment violation, or 
other reasons in cohort B. Therefore, a maximum of 36 patients will be accrued 
to cohort B for an overall maximum of 87 patients for the entire study. 
 
16.13 
Accrual Rate and Study Duration:  The anticipated accrual rate is 3-4 evaluable 
multiple myeloma patients per month.  At this rate, it will likely take about 2.5 
months to enroll, treat, and evaluate each cohort in the phase I portion of this 
study.  The phase I portion is expected to take between 5 and 10 months.  The 
phase II portion of this study will accrue in the subsequent 1 year.  The maximum 
total study duration is expected to be approximately 3 years, or until the last 
patient accrued has been observed for at least 12 months.   
 
As of Addendum 9,   it is anticipated that the accrual rate in cohort B is 3-4 
evaluable light chain amyloidosis patients per month.  It is anticipated that cohort 
B will accrue in approximately 12 months. The maximum total study duration is 


 
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expected to be approximately 2 years after Addendum 8 is activated, or until the 
last patient accrued has been observed for at least 12 months.   
 
 
 
Phase I Portion  
 
16.2 
Study Design:  The phase I study is designed to determine the maximally tolerated dose 
(MTD) and toxicity profile of Ixazomib in combination with cyclophosphamide and 
dexamethasone in patients with previously untreated multiple myeloma using the 
standard cohort 3+3 design. Three patients will be treated at each dose level and observed 
for a minimum of four weeks (i.e. one full cycle) before new patients are treated.  Doses 
will not be escalated in any individual patient. 
 
16.21  
MTD Definition: MTD is defined as the dose level below the lowest dose that 
induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 
of a maximum of 6 new patients). A total of 6 patients treated at the MTD will 
be sufficient to identify common toxicities at the MTD. For instance, those 
toxicities with an incidence of at least 25% will be observed with a probability 
of at least 82% (1-(1-0.25)6). 
 
Refer to Section 7.52 for definition of dose-limiting toxicity (DLT). 
 
16.22 
MTD Determination: 
 
Dose Escalation:  The phase I portion of this study will utilize a standard cohort 
of three design.   The dose levels to which patients will be assigned in sequential 
cohorts are described in Section 7.51.   The first cohort of three patients will be 
treated at dose level 0.  Decisions on when and how to dose escalate are 
described below. 
 
16.221  Three patients will be treated at a given dose level combination and 
observed for 1 cycle to assess toxicity.  
 
16.222  If DLT is not seen in any of the 3 patients, 3 new patients will be 
accrued and treated at the next higher dose level. If DLT is seen in 2 or 
3 of 3 patients treated at a given dose level, then the next 3 patients 
will be treated at the next lower dose level, if only 3 patients were 
enrolled and treated at this lower dose level.  
 
16.223  If DLT is seen in 1 of 3 patients treated at a given dose level, up to 3 
additional patients will be enrolled and treated at the same dose level. 
If DLT is seen in at least one of these additional three patients (≥2 of 
6), the MTD will have been exceeded and further accrual will cease to 
this cohort. If dose-limiting toxicity (DLT) is not seen in any of the 
three additional patients, 3 new patients will be accrued and treated at 
the next higher dose level.  
 
16.224  After enrolling 6 patients on a specific dose level, if DLT is observed 
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defined as the previous dose unless only 3 patients were treated at the 
lower dose level. In that case, 3 additional patients will be treated at 
this lower dose level such that a total of 6 patients are treated at the 
MTD to more fully assess the toxicities associated with the MTD. 
 
16.225  Dose de-escalation: If dose-limiting toxicity meets the stopping 
boundaries set by the above dose escalation algorithm at dose level 0 
(for example, more than 1 out of 3 patients or more than 1 out of 6 
patients), the next cohort of three patients will be entered at a dose 
level of -1. If dose level -1 meets the stopping boundaries, the next 
cohort of three patients will be entered at dose level -2.  Further dose 
re-escalation will depend on the toxicity profile observed at these dose 
levels, and re-evaluation of the regimen by the study team may be 
done. 
 
16.226  If a patient fails to complete the first cycle of treatment for reasons 
other than toxicity, the patient will be regarded as inevaluable and will 
be replaced.    
 
16.227  Operating Characteristics for standard cohort of 3 design: The following 
table gives the probability of dose escalation at a single dose level as a 
function of the true probability of DLT at that level using the cohorts 
of 3 design described above. 
 
True Rate 
of DLT (%) 
 
Probability of Dose Escalation 
10 
0.91 
20 
0.71 
30 
0.49 
40 
0.31 
50 
0.17 
 
 
 
16.23 Analysis Plans: All the relevant results pertaining to toxicity, MTD, response, 
timed endpoints and laboratory correlates will be examined in an exploratory 
and hypothesis-generating fashion. The small sample size and the heterogeneous 
patient population associated with phase I studies restricts the generalizability of 
the results. Any notable statistical result should only be viewed as preliminary 
evidence for further study in Phase II trials rather than a definitive finding in and 
of itself. 
 
16.231  Adverse Events Profile 
 
The number and severity of all adverse events (overall and by dose-
level) will be tabulated and summarized in this patient population. The 
Grade 3+ adverse events will also be described and summarized in a 


 
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similar fashion. This will provide an indication of the level of tolerance 
for this treatment combination in this patient group.  
 
16.232  Toxicity Profile 
 
The term toxicity is defined as adverse events that are classified as 
either possibly, probably, or definitely related to study treatment.  Non-
hematologic toxicities will be evaluated via the ordinal CTC standard 
toxicity grading. Hematologic toxicity measures of thrombocytopenia, 
neutropenia, and leukopenia will be assessed using continuous variables 
as the outcome measures (primarily nadir) as well as categorization via 
CTC standard toxicity grading. 
  
Overall toxicity incidence as well as toxicity profiles by dose level, 
patient and tumor site will be explored and summarized. Frequency 
distributions, graphical techniques and other descriptive measures will 
form the basis of these analyses.  
 
 
16.233  Response Profile   
 
A response is defined to be a CR, VGPR, or PR noted as the objective 
status.  Response will be evaluated using all cycles of treatment.  All 
patients meeting the eligibility criteria who have signed a consent form 
and have begun treatment will be evaluable for response.  
 
Responses will be summarized by simple descriptive summary statistics 
delineating complete and partial responses as well as stable and 
progressive disease in this patient population.  
 
Phase II Portion  
 
16.3  
Statistical Design: 
 
 
 
Cohort A (multiple myeloma): 
 
16.31 Decision Rule:   
 
A combination of lenalidomide plus dexamethasone, an oral regimen, is the 
mainstay therapy for newly diagnosed multiple myeloma.  In a large multi-center 
study, 208 patients were evaluated for response to treatment with lenalidomide 
plus low dose dexamethasone.8  Eighty-four patients (40%) achieved a complete 
or very good partial response.  Ixazomib in combination with cyclophosphamide 
and dexamethasone is another fully oral regimen.  An increase in the rate of 
complete plus very good partial response compared to lenalidomide plus 
dexamethasone would be of interest.    
 
The largest success proportion where the proposed treatment regimen would be 
considered ineffective in this population is 40%, and the smallest success 


 
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proportion that would warrant subsequent studies with the proposed regimen in 
this patient population is 60%. The following one-stage binomial design requires 
41 evaluable patients (35 from phase II and 6 from the MTD portion of phase I) 
to test the null hypothesis that the true success proportion in this patient 
population is at most 40%.  
 
 
16.311 
Final Decision Rule:  If 20 or fewer successes are observed in the first 
41 evaluable patients, we will consider this regimen ineffective in this 
patient population. Otherwise, if the number of successes is at least 21, 
this will be considered evidence of promising activity and the 
treatment may be recommended for further testing in subsequent 
studies.    
16.312 
Over Accrual: If more than the target number of patients are accrued, 
the additional patients will not be used to evaluate the stopping rule or 
used in any decision making process.  Analyses involving over accrued 
patients are discussed in Section 16.44. 
 
16.32 Power and Significance Level:  Assuming that the number of successes is 
binomially distributed, the significance level is .10, i.e. there is a 10% chance of 
finding the drug to be effective when it truly is not.  The probability of declaring 
that this regimen warrants further study (i.e. statistical power) under various 
success proportions can be tabulated as a function of the true success proportion 
as shown in the following table. 
 
If the true success proportion is... 
0.40 
0.45 
0.50 
0.55 
0.60 
Then the probability of declaring 
that the regimen warrants further 
study is… 
0.10 
0.26 
0.50 
0.74 
0.90 
 
16.33 Other considerations:  Adverse events, quality/duration of response, and patterns 
of treatment failure observed in this study, as well as scientific discoveries or 
changes in standard care will be taken into account in any decision to terminate 
the study.  
 
Cohort B (light chain amyloidosis): 
 
16.34  Decision Rule:   
 
The largest success proportion where the proposed treatment regimen would be 
considered ineffective in this population is 30%, and the smallest success 
proportion that would warrant subsequent studies with the proposed regimen in 
this patient population is 50%. The following one-stage binomial design requires 
33 evaluable patients to test the null hypothesis that the true success proportion in 
this patient population is at most 30%.  
 
16.341 
Final Decision Rule:  If 13 or fewer successes are observed in the first 
33 evaluable patients, we will consider this regimen ineffective in this 
patient population. Otherwise, if the number of successes is at least 14, 


 
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this will be considered evidence of promising activity and the 
treatment may be recommended for further testing in subsequent 
studies.    
 
16.342 
Over Accrual: If more than the target number of patients are accrued, 
the additional patients will not be used to evaluate the stopping rule or 
used in any decision making process.  Analyses involving over accrued 
patients are discussed in Section 16.44. 
 
16.35 Power and Significance Level:  Assuming that the number of successes is 
binomially distributed, the significance level is .09, i.e. there is a 9% chance of 
finding the drug to be effective when it truly is not.  The probability of declaring 
that this regimen warrants further study (i.e. statistical power) under various 
success proportions can be tabulated as a function of the true success proportion 
as shown in the following table. 
 
If the true success proportion is... 
0.30 
0.35 
0.40 
0.45 
0.50 
Then the probability of declaring 
that the regimen warrants further 
study is… 
0.09 
0.24 
0.45 
0.68 
0.85 
 
16.36 Other considerations:  Adverse events, quality/duration of response, and patterns 
of treatment failure observed in this study, as well as scientific discoveries or 
changes in standard care will be taken into account in any decision to terminate 
the study. 
 
 
16.4 
Analysis Plan 
 
16.41 Primary Outcome Analyses: 
 
16.411 Definition:  For cohort A, the   primary endpoint in the phase II portion 
of this trial is the proportion of complete plus very good partial 
responses.  A success is defined as a  sCR, CR or VGPR noted as the 
objective status on two consecutive evaluations.  For cohort B of the 
phase II portion, the primary endpoint is the rate of hematologic 
response.   A success will be defined as an sCR, ACR, VGPR, or PR      
noted as the objective status on two consecutive evaluations.  Response 
will be evaluated using the first 12 cycles (induction therapy). All 
patients meeting the eligibility criteria who have signed a consent form 
and have begun treatment will be evaluable for response. 
 
16.412 Estimation:  In each cohort independently, the proportion of successes 
will be estimated by the number of successes divided by the total number 
of evaluable patients. Exact binomial 95% confidence intervals for the 
true success proportions will be calculated. 
 
16.42 Secondary Outcome Analyses (to be evaluated in each cohort independently) 
 


 
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16.421 Survival time is defined as the time from registration to death due to any 
cause. The distribution of survival time will be estimated using the 
method of Kaplan-Meier33.  
 
16.422    Progression-free survival is defined as the time from registration to the 
earliest date of documentation of disease progression or death due to 
any cause. The distribution of progression-free survival will be 
estimated using the method of Kaplan-Meier 
 
16.423 Adverse Events:  All eligible patients that have initiated treatment will be 
considered evaluable for assessing adverse event rate(s).  The maximum 
grade for each type of adverse event will be recorded for each patient, 
and frequency tables will be reviewed to determine patterns.  
Additionally, the relationship of the adverse event(s) to the study 
treatment will be taken into consideration. 
 
16.424 Cohort B only:  For each disease site (heart, renal, liver, neuropathy), the 
organ response rate will be estimated by the total number of patients who 
have an organ response divided by the total number of evaluable patients 
who had involvement in that organ at baseline.  Exact binomial 95% 
confidence intervals for the true organ response rates will be calculated.   
 
16.43   Correlative Analyses 
 
16.431  Cohort A only:  Individual and mean plasma concentration data will be 
plotted over time. A summary table will be presented for the plasma 
concentration data. PK parameters will be estimated using 
noncompartmental analysis methods. The plasma PK parameters 
calculated for individual plasma Ixazomib concentration-time data will 
include, but are not limited to: Cmax, Tmax, and AUC. PK parameters 
will be summarized using descriptive statistics. 
 
16.432 The FACT/GOG neurotoxicity questionnaire will be completed by 
patients at baseline, after each cycle for the first 4 cycles, and then every 
three cycles.  Patients will be evaluated by overall score at each time 
point and changes over time will be calculated.  These measures will be 
correlated with outcome using Fisher’s exact test and Kaplan-Meier 
methods where appropriate. 
 
16.44 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used in any 
decision making processes; however, they will be included in final endpoint 
estimates and confidence intervals. 
 
16.5 
Data & Safety Monitoring: 
 
16.51 The principle investigator(s) and the study statistician will review the study at 
least twice a year to identify accrual, adverse event, and any endpoint problems 
that might be developing. The Mayo Clinic Cancer Center (MCCC) Data Safety 


 
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Monitoring Board (DSMB) is responsible for reviewing accrual and safety data 
for this trial at least twice a year, based on reports provided by the MCCC 
Statistical Office. 
 
16.52 Adverse Event Stopping Rules (includes all phase II patients, including phase I 
patients treated at the MTD to be evaluated in each phase II cohort separately):   
The stopping rules specified below are based on the knowledge available at study 
development.  We note that the Adverse Event Stopping Rule may be adjusted in 
the event of either (1) the study re-opening to accrual or (2) at any time during 
the conduct of the trial and in consideration of newly acquired information 
regarding the adverse event profile of the treatment(s) under investigation.  The 
study team may choose to suspend accrual because of unexpected adverse event 
profiles that have not crossed the specified rule below. 
 
Accrual will be temporarily suspended to this study if at any time we observe 
events considered at least possibly related to study treatment (i.e. an adverse 
event with attribute specified as  “possible,” “probable,” or “definite”) that 
satisfy one of the following: 
 
• 
if 5 or more patients in the first 15 treated patients experience a grade 4 or 
higher non-hematologic adverse event at least possibly related to treatment. 
 
• 
if after the first 15 patients have been treated, 40% of all patients experience 
a grade 4 or higher non-hematologic adverse event at least possibly related to 
treatment.  
 
We note that we will review grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the emergence 
of a previously unrecognized treatment-related adverse event. 
 
16.6   Results Reporting on ClinicalTrials.gov: At study activation, this study will have been 
registered within the “ClincialTrails.gov” website. The Primary and Secondary Endpoints 
along with other required information for this study will be reported on 
www.ClinicalTrials.gov. For purposes of timing of the Results Reporting, the initial 
estimated completion date for the Primary Endpoint of this study is 2 years after the study 
opens to accrual to cohort B. The definition of “Primary Endpoint Completion Date” 
(PECD) for this study is at the time the last patient registered has been followed for at 
least 12 months. 
 
16.7 
Inclusion of Women and Minorities 
 
16.71 This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
 
16.72 There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, and there is no reason to 
expect such differences to exist. Therefore, although the planned analysis will, as 
always, look for differences in treatment effect based on racial and gender 


 
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groupings, the sample size is not increased in order to provide additional power 
for subset analyses. 
 
16.73 The geographical region served by MCCC has a population which includes 
approximately 3% minorities.  Based on prior MCCC studies involving similar 
disease sites, we expect about 3-5% of patients will be classified as minorities by 
race and about 33% of patients will be women. Expected sizes of racial by 
gender subsets are shown in the following table: 
 
Accrual Estimates by Gender/Ethnicity/Race  
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
0 
1 
0 
1 
Not Hispanic or Latino 
29 
57 
0 
86 
Ethnic Category: Total of all subjects* 
29 
58 
0 
87 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
Black or African American 
1 
1 
0 
2 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
White 
28 
57 
0 
85 
Racial Category: Total of all subjects* 
29 
58 
0 
87 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa.  Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 
 


 
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17.0  
Pathology Considerations/Tissue Biospecimens   
 
None 
 
18.0 
Records and Data Collection Procedures   
 
 
18.1 
Submission Timetable 
 
Initial Material(s)  
Case Report Form (CRF) 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
On-Study Form: Multiple Myeloma  
 
 
 
 
≤2 weeks after registration 
On-Study Form: Amyloidosis  
Baseline Adverse Event Form 
Pretreatment Measurement Form: Multiple 
Myeloma 
Pretreatment Measurement Form: Amyloidosis  
Patient Questionnaire Booklet Compliance Form1 
SPEP, UPEP, FLC , Serum and Urine 
Immunofixation, Bone Marrow biopsy and 
aspirate, X-Ray skeletal survey,  Plasma Cell 
Proliferation and Assessment, Cytogenetic, FISH 
on study reports 
End of Active Treatment/Cancel Notification 
Form 
Submit ≤2 weeks after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
Patient Questionnaire Booklet2 
≤2 weeks after registration 
Patient questionnaire booklet must be used; copies are not 
acceptable for this submission. 
 
1. This form must be completed only if the Quality of Life Patient Questionnaire contains absolutely 
NO patient provided assessment information. 
2. Patient questionnaire booklet must be used; copies are not acceptable for this submission. 
 
Test Schedule Material(s) 
. 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 


 
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At each evaluation 
during treatment 
At end of treatment 
 
Evaluation/Treatment Form: Cohort A (Multiple 
Myeloma)  
X 
X 
Evaluation/Treatment Form:  Cohort B 
(Amyloidosis) 
X 
X 
Stem Cell Harvest Form (optional) 
X3 
 
Nadir/Adverse Event Form 
X 
X 
Measurement Form: Multiple Myeloma  
X 
X 
Measurement Form: Amyloidosis  
X 
X 
SPEP, UPEP, FLC , Serum and Urine  
Immunofixation, Bone Marrow biopsy and aspirate, 
X-Ray skeletal survey 
X4 
X4 
Research Blood Submission Form 
X (see Section 
14.0)5 
 
Patient Questionnaire Booklet  
X1, 5 
 
Patient Questionnaire Booklet Compliance Form 
X2 
 
End of Active Treatment/Cancel Notification Form 
 
X 
ADR/AER 
At each 
occurrence 
(see Section 10.0) 
 
1.  Patient questionnaire booklet must be used; copies are not acceptable for this submission. (see 
Section 4.0). 
2. This form must be completed only if the Quality of Life Patient Questionnaire contains absolutely 
NO patient provided assessment information. (see Section 4.0). 
3. May interrupt therapy for stem cell collection at any time after 3 cycles of Induction treatment 
(see Schema).  Submit the Stem Cell Harvest Form after stem cell collection has been completed. 
4. Submission of these reports is only required for documentation of CR or progression.  For 
documentation of CR, submit all of these reports at the first confirmation of CR.  For 
documentation of progression, submit one report for one of the measures where progression was 
seen.   Attention: 
. 
5. Only when required by the Test Schedule (see Section 4.0). 
 
Follow-up Material(s)  
CRF 
Event Monitoring Phase1 
 
 
q. 3 months 
until PD or 
subsequent 
treatment for 
myeloma 
 
At PD or 
subsequent 
treatment 
for 
myeloma 
 
After PD or 
subsequent 
treatment 
for 
myeloma q. 
6 mos. 
 
 
 
Death 
 
 
 
New Primary 
Event Monitoring Form 
X 
X 
X 
X 
At each occurrence 


 
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1. If a patient is still alive 5 years after registration, no further follow-up is required. 
 
 
19.0  
Budget 
 
19.1 
Costs charged to patient:  routine clinical care, study drugs cyclophosphamide and 
dexamethasone 
 
19.2 
Tests to be research funded: Study drug Ixazomib, Pharmacokinetic sampling (cohort 
A only) 
 
 
19.3 
Other budget concerns: None 
 
20.0 
References 
 
1. 
Adams J, Behnke M, Chen S, et al. Potent and selective inhibitors of the proteasome: dipeptidyl 
boronic acids. Bioorganic & medicinal chemistry letters. 1998;8(4):333-338. 
2. 
Adams J, Palombella VJ, Sausville EA, et al. Proteasome inhibitors: a novel class of potent and 
effective antitumor agents. Cancer research. 1999;59(11):2615-2622. 
3. 
Adams J. Development of the proteasome inhibitor PS-341. The oncologist. 2002;7(1):9-16. 
4. 
Richardson PG, Hideshima T, Anderson KC. Bortezomib (PS-341): a novel, first-in-class 
proteasome inhibitor for the treatment of multiple myeloma and other cancers. Cancer control. 
2003;10(5):361-369. 
5. 
Kumar S. Multiple myeloma - current issues and controversies. Cancer Treat Rev. 2010;36 Suppl 
2:S3-11. 
6. 
Kumar SK, Mikhael JR, Buadi FK, et al. Management of newly diagnosed symptomatic multiple 
myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus 
guidelines. Mayo Clin Proc. 2009;84(12):1095-1110. 
7. 
Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the 
impact of novel therapies. Blood. 2008;111(5):2516-2520. 
8. 
Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone 
versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple 
myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010;11(1):29-37. 
9. 
Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone 
combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116(5):679-686. 
10. 
Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone 
compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy 
after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised 
phase 3 study. Lancet. 2010;376(9758):2075-2085. 
11. 
San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for 
initial treatment of multiple myeloma. N Engl J Med. 2008;359(9):906-917. 
12. 
Reeder CB, Reece DE, Kukreti V, et al. Cyclophosphamide, bortezomib and dexamethasone 
induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. 
Leukemia. 2009;23(7):1337-1341. 
13. 
Kumar SK, Flinn I, Noga SJ, et al. Bortezomib, dexamethasone, cyclophosphamide and 
lenalidomide combination for newly diagnosed multiple myeloma: phase 1 results from the multicenter 
EVOLUTION study. Leukemia. 2010;24(7):1350-1356. 


 
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14. 
Kumar S, Flinn IW, Richardson PG, et al. Novel Three- and Four-Drug Combination Regimens 
of Bortezomib, Dexamethasone, Cyclophosphamide, and Lenalidomide, for Previously Untreated 
Multiple Myeloma: Results From the Multi-Center, Randomized, Phase 2 EVOLUTION Study. ASH 
Annual Meeting Abstracts. 2010;116(21):621-. 
15. 
Gupta N, Liu G, Berg D, Kalebic T, Gomez-Navarro J. Clinical Pharmacokinetics of Intravenous 
and Oral Ixazomib, An Investigational Proteasome Inhibitor: An Analysis of Data From Four Phase 1 
Monotherapy Studies. Blood (ASH Annual Meeting Abstracts). 2010;116(21):abstr 1813. 
16. 
Gupta N, Saleh M, Venkatakrishnan K. Flat-Dosing Versus BSA-Based Dosing for Ixazomib, An 
Investigational Proteasome Inhibitor: Population Pharmacokinetic (PK) Analysis of Pooled Data From 4 
Phase-1 Studies 53rd ASH Annual Meeting and Exposition. San Diego, CA; 2011:abstr 1433. 
17. 
Lonial S, Baz RC, Wang M, et al. Phase I study of twice-weekly dosing of the investigational oral 
proteasome inhibitor Ixazomib in patients (pts) with relapsed and/or refractory multiple myeloma (MM). 
ASCO Meeting Abstracts. 2012;30(15_suppl):8017. 
18. 
Kumar S, Bensinger W, Reeder CB, et al. Weekly dosing of the investigational oral proteasome 
inhibitor Ixazomib in patients (pts) with relapsed/refractory multiple myeloma (MM): A phase I study. 
ASCO Meeting Abstracts. 2012;30(15_suppl):8034. 
19. 
Kumar SK, Berdeja JG, Niesvizky R, et al. A Phase 1/2 Study of Weekly Ixazomib, an 
Investigational Oral Proteasome Inhibitor, in Combination with Lenalidomide and Dexamethasone in 
Patients with Previously Untreated Multiple Myeloma (MM). ASH Annual Meeting Abstracts. 
2012;120(21):332-. 
20. 
Cunningham D, Powles R, Malpas J, et al. A randomized trial of maintenance interferon 
following high-dose chemotherapy in multiple myeloma: long-term follow-up results. Br J Haematol. 
1998;102(2):495-502. 
21. 
Attal M, Harousseau JL, Leyvraz S, et al. Maintenance therapy with thalidomide improves 
survival in patients with multiple myeloma. Blood. 2006;108(10):3289-3294. 
22. 
Spencer A, Prince HM, Roberts AW, et al. Consolidation therapy with low-dose thalidomide and 
prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-
cell transplantation procedure. J Clin Oncol. 2009;27(11):1788-1793. 
23. 
Lokhorst HM, van der Holt B, Zweegman S, et al. A randomized phase III study on the effect of 
thalidomide combined with Adriamycin, dexamethasone (TAD), and high-dose melphalan, followed by 
thalidomide maintenance in patients with multiple myeloma. Blood. 2009. 
24. 
Stewart AK, Trudel S, Bahlis NJ, et al. A Randomized Phase III Trial of Thalidomide and 
Prednisone as Maintenance Therapy Following Autologous Stem Cell Transplantation (ASCT) In Patients 
with Multiple Myeloma (MM): The NCIC CTG MY.10 Trial. ASH Annual Meeting Abstracts. 
2010;116(21):39-. 
25. 
Attal M, Lauwers Vc, Marit G, et al. Maintenance Treatment with Lenalidomide After 
Transplantation for MYELOMA: Final Analysis of the IFM 2005-02. ASH Annual Meeting Abstracts. 
2010;116(21):310-. 
26. 
McCarthy PL, Owzar K, Anderson KC, et al. Phase III Intergroup Study of Lenalidomide Versus 
Placebo Maintenance Therapy Following Single Autologous Hematopoietic Stem Cell Transplantation 
(AHSCT) for Multiple Myeloma: CALGB 100104. ASH Annual Meeting Abstracts. 2010;116(21):37-. 
27. 
Palumbo A, Delforge M, Catalano J, et al. A Phase 3 Study Evaluating the Efficacy and Safety of 
Lenalidomide Combined with Melphalan and Prednisone In Patients  65 Years with Newly Diagnosed 
Multiple Myeloma (NDMM): Continuous Use of Lenalidomide Vs Fixed-Duration Regimens. Blood 
(ASH Annual Meeting Abstracts). 2010;116: Abstract 622. 
28. 
Palumbo A, Bringhen S, Cavalli M, et al. Bortezomib, Melphalan, Prednisone and Thalidomide 
Followed by Maintenance with Bortezomib and Thalidomide (VMPT-VT) for Initial Treatment of Elderly 


 
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Multiple Myeloma Patients: Updated Follow-up and Impact of Prognostic Factors. ASH Annual Meeting 
Abstracts. 2010;116(21):620-. 
29. 
Mateos M-V, Oriol A, Martinez J, et al. A Prospective, Multicenter, Randomized, Trial of 
Bortezomib/Melphalan/Prednisone (VMP) Versus Bortezomib/Thalidomide/Prednisone (VTP) as 
Induction Therapy Followed by Maintenance Treatment with Bortezomib/Thalidomide (VT) Versus 
Bortezomib/Prednisone (VP) in Elderly Untreated Patients with Multiple Myeloma Older Than 65 Years. 
ASH Annual Meeting Abstracts. 2009;114(22):3-. 
30. 
Berdeja JG, Richardson PG, Lonial S, et al. Phase 1/2 Study of Oral Ixazomib, A Novel, 
Investigational Proteasome Inhibitor, in Combination with Lenalidomide and Dexamethasone in Patients 
with Previously Untreated Multiple Myeloma (MM). ASH Annual Meeting Abstracts. 2011;118(21):479-. 
31. 
Kumar S, Bensinger WI, Reeder CB, et al. Weekly Dosing of the Investigational Oral Proteasome 
Inhibitor Ixazomib in Patients with Relapsed and/or Refractory Multiple Myeloma: Results From a Phase 
1 Dose-Escalation Study. ASH Annual Meeting Abstracts. 2011;118(21):816-. 
32. 
Richardson PG, Baz R, Wang L, et al. Investigational Agent Ixazomib, An Oral Proteasome 
Inhibitor, in Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (MM): Results From the 
Expansion Cohorts of a Phase 1 Dose-Escalation Study. ASH Annual Meeting Abstracts. 
2011;118(21):301-. 
33. 
Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 
1958;53:457-481. 
 


MC1382 
Appendix I 
 
Page 1 of 1 
 
Protocol Version Date:  March 22, 2017 
 
 
Mayo Risk Stratification 
 
 
 
 
 
 
 
 
 
 
 
 
 
High Risk 
FISH deletion 17p 
FISH t(14; 16) 
FISH t(14; 20) 
GEP (if done)  High risk signature 
 


MC1382 
Appendix II 
 
Page 1 of 1 
 
Protocol Version Date:  March 22, 2017 
 
NYHA Classification 
 
Class I:  
NO Symptoms with ordinary activity  
Class II:  Symptoms with ordinary activity  
Class III:  Symptoms with minimal activity 
Class IV:  Symptoms at rest 
 


MC1382 
Appendix III 
 
Page 1 of 1 
 
Protocol Version Date:  March 22, 2017 
 
Multiple Myeloma Diagnostic Criteria 
 
Standard criteria for a diagnosis of multiple myeloma are as follows (Kyle et al British Journal 
of Haematology. 121(5):749-57, 2003)  
 
Multiple Myeloma 
Monoclonal protein present in serum ≥ 3 g/dl 
and/or 
Bone marrow clonal plasma cells ≥ 10% 
 
Myeloma-related organ or tissue impairment (ROTI) 
Calcium 1 mg/dL (0.25 mmol/L) above the upper limit of normal 
Creatinine > 2 mg/dL (173 mmol/L) 
Lytic bone lesions or osteoporosis 
 
Asymptomatic myeloma 
Multiple myeloma and absence of ROTI 
 
Symptomatic myeloma 
Multiple myeloma and presence of any ROTI that can be attributed to myeloma. 
 






MC1382 
Appendix V 
 
 
 
Protocol Version Date:  March 22, 2017 
 
 
 
 
You have been given a booklet to complete for this study.  The booklet contains some 
questions about your ‘quality of life’ as a patient receiving treatment for cancer.  You 
answers will help us to better understand how the treatment you are receiving is affecting 
the way you feel. 
 
 
1. The booklet contains one set of questions: 
a. (11 questions) FACT-GOG Neurotoxicity questionnaire 
 
2. Directions on how to complete the set of questions is written on the top of the set. 
 
3. Please complete the booklet during your scheduled clinical visit and return it to your 
nurse  or your physician 
 
 
 
Thank you for taking the time to help us. 
 
 
 
 


MC1382 
 
Appendix V 
 
 
   Page 2 of 2  
Protocol Version Date:  March 7, 2017 
 
 
FACT/GOG-NTX (Version 4) 
 
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
 
 
ADDITIONAL CONCERNS 
 
Not 
at all 
A 
little 
bit 
Some
-what 
Quite 
a bit 
Very 
much 
I have numbness or tingling in my hands ............................
0 
1 
2 
3 
4 
I have numbness or tingling in my feet ...............................
0 
1 
2 
3 
4 
I feel discomfort in my hands ..............................................
0 
1 
2 
3 
4 
I feel discomfort in my feet .................................................
0 
1 
2 
3 
4 
I have joint pain or muscle cramps .....................................
0 
1 
2 
3 
4 
I feel weak all over ..............................................................
0 
1 
2 
3 
4 
I have trouble hearing ..........................................................
0 
1 
2 
3 
4 
I get a ringing or buzzing in my ears ...................................
0 
1 
2 
3 
4 
I have trouble buttoning buttons .........................................
0 
1 
2 
3 
4 
I have trouble feeling the shape of small objects when 
they are in my hand .............................................................
 
0 
 
1 
 
2 
 
3 
 
4 
I have trouble walking .........................................................
0 
1 
2 
3 
4 
 


MC1382 
Appendix VI 
 
 
 
Protocol Version Date:  March 22, 2017 
Millennium Pregnancy Reporting Form 
 
 
 
 
 


MC1382 
Appendix VI 
 
 
 
Protocol Version Date:  March 22, 2017 
 
 
 
 
 
 


MC1382 
Appendix VI 
 
 
 
Protocol Version Date:  March 22, 2017 
 
 
 
 
 
 
 


MC1382 
Appendix VI 
 
 
 
Protocol Version Date:  March 22, 2017 
 
 
 
 
 
 
 
 
 
 


MC1382 
 
Appendix VII 
 
 
  
Protocol Version Date:  March 7, 2017 
 
 
 
 
ECOG Performance Status Scale 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 1 
 
SCORE  
DESCRIPTION  
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 
housework, 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.  
 
 
 

ICF_001.pdf: 
 
 
 
 
 
MC1382 / 13-000414 
 
 
Phase 1/2 Trial of MLN9708 in Combination With 
Cyclophosphamide and Dexamethasone in Patients With 
Previously Untreated Symptomatic Multiple Myeloma 
 
 
NCT01864018 
 
 
Document Date: 01/06/2022 


 
 
Approval Date:  
January 6, 2022 
Not to be used after: February 24, 2022 
 
IRB#: 13-000414 01 
Page 1 of 17 
IRB Doc. Ctrl # 10013.28 
 
 
 
 
 
 
 
Name and Clinic Number 
 
RESEARCH PARTICIPANT CONSENT AND PRIVACY 
AUTHORIZATION FORM 
 
Study Title: MC1382: Cohort B-Phase 1/2 Trial of (MLN9708) ixazomib in Combination with 
Cyclophosphamide and Dexamethasone in Patients with Previously Untreated 
Symptomatic Multiple Myeloma or Light Chain Amyloidosis (Amyloidosis 
patients) 
 
IRB#:  
13-000414  
 
Principal Investigator: Dr. S. Kumar and Colleagues 
 
Please read this information carefully. It tells you important things about this research study. A 
member of our research team will talk to you about taking part in this research study.  If you 
have questions at any time, please ask us. 
 
Take your time to decide.  Feel free to discuss the study with your family, friends, and healthcare 
provider before you make your decision.   
 
To help you decide if you want to take part in this study, you should know: 
• Taking part in this study is completely voluntary.  
• You can choose not to participate.  
• You are free to change your mind at any time if you choose to participate.   
• Your decision won’t cause any penalties or loss of benefits to which you’re otherwise 
entitled. 
• Your decision won’t change the access to medical care you get at Mayo Clinic now or in 
the future if you choose not to participate or discontinue your participation.   
 
For purposes of this form, Mayo Clinic refers to Mayo Clinic in Arizona, Florida and Rochester, 
Minnesota; Mayo Clinic Health System; and all owned and affiliated clinics, hospitals, and 
entities. 
 
If you decide to take part in this research study, you will sign this consent form to show that you 
want to take part. We will give you a copy of this form to keep. A copy of this form will be put 
in your medical record. 
 
 
 


 
 
Approval Date:  
January 6, 2022 
Not to be used after: February 24, 2022 
 
IRB#: 13-000414 01 
Page 2 of 17 
IRB Doc. Ctrl # 10013.28 
 
 
 
 
 
 
 
Name and Clinic Number 
 
CONTACT INFORMATION 
 
 
You can contact … 
At … 
If you have questions about … 
Principal Investigators: 
Dr. Shaji Kumar 
 
 
 
 
 
 
 
Dr. Leif Bergsagel 
 
Phone: 
(507) 284-2511 
 
Institution Name and Address: 
Mayo Clinic  
200 First Street SW 
Rochester, MN 55905 
 
Phone: 
(480) 301-8000 
 
Institution Name and Address: 
Mayo Clinic in Arizona 
13400 East Shea Boulevard 
Scottsdale, AZ 85259 
 Study tests and procedures 
 Research-related injuries or 
emergencies 
 Any research-related concerns or 
complaints 
 Withdrawing from the research study 
 Materials you receive 
 Research-related appointments 
Mayo Clinic 
Institutional Review 
Board (IRB) 
Phone: 
(507) 266-4000 
 
Toll-Free: 
(866) 273-4681 
 Rights of a research participant 
 
Research Subject 
Advocate 
(The RSA is independent 
of the Study Team) 
Phone: 
(507) 266-9372 
 
Toll-Free: 
(866) 273-4681 
 
E-mail: 
researchsubjectadvocate@mayo.edu 
 Rights of a research participant 
 Any research-related concerns or 
complaints 
 Use of your Protected Health 
Information 
 Stopping your authorization to use 
your Protected Health Information 
 Withdrawing from the research study 
Patient Account Services 
 
Toll-Free: (844) 217-9591 
 
 Billing or insurance related to this 
research study 
 
 
 


 
 
Approval Date:  
January 6, 2022 
Not to be used after: February 24, 2022 
 
IRB#: 13-000414 01 
Page 3 of 17 
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Name and Clinic Number 
Other Information:  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
 
1. 
Why are you being asked to take part in this research study? 
 
 
You are being asked to take part in this study because you have been diagnosed with a condition 
called Light Chain Amyloidosis that requires treatment.  
 
The plan is to have about 87 people take part in this study at Mayo Clinic. 
 
 
2. 
Why is this research study being done? 
 
 
Various treatment options are available for treatment of your condition. One of the commonly 
used treatments is the combination of a drug called bortezomib with two other drugs, 
cyclophosphamide and dexamethasone.  Ixazomib is similar to bortezomib (VELCADE), but can 
be given as a pill instead of injection. It is thought that Ixazomib will interfere with the process 
of protein breakdown in the plasma cells that are responsible for the light chain amyloidosis. 
This study is being done to find out the effects (good and bad) of treating amyloidosis with the 
combination of Ibixazomib, cyclophosphamide and dexamethasone.   
 
The drug (Ixazomib) as used in this study is considered investigational, which means it has either 
not been approved by the Food and Drug Administration (FDA) for routine clinical use or for the 
use described in this study, however the FDA has approved the use in this research study. 
 
Cyclophosphamide and dexamethasone are both FDA approved, however their use in this 
research study is considered investigational. 
 
 
 


 
 
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January 6, 2022 
Not to be used after: February 24, 2022 
 
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Name and Clinic Number 
 
3. 
Information you should know 
 
 
Who is Funding the Study? 
Takeda Pharmaceuticals is funding the study.  Takeda will pay the Principal Investigator or the 
institution to cover costs related to running the study. 
 
 
4. 
How long will you be in this research study? 
 
 
You will be in the study for approximately three years. 
 
 
5. 
What will happen to you while you are in this research study? 
 
 
If you agree to be in the study, you will be asked to participate in the following: 
 
Screening 
• Complete medical history, physical exam, including, weight, vitals and height and 
assessment of your ability to carry out daily activities. 
• Routine Blood and urine tests 
• Skeletal survey 
• Bone marrow aspirate and biopsy 
• Chest x-ray 
• Echocardiogram 
• Neurological examination and nerve studies if there is nerve involvement 
• Scan of the abdomen if there is suspicion of liver enlargement 
• Pregnancy test  
• A questionnaire to assess if you have any symptoms suggesting damage to the nerves 
 
Every Cycle, Pretreatment 
• Physical Exam, including, weight, vitals and height and assessment of your ability to 
carry out daily activities  
• Routine Blood and urine tests 
• A questionnaire to assess if you have any symptoms suggesting damage to the nerves 
(every cycle for the first 4 cycles, and then every 3 cycles) 


 
 
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January 6, 2022 
Not to be used after: February 24, 2022 
 
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• Patient medication diary 
• 
X-ray skeletal survey (every 6 cycles) 
 
Every 14 days (for 3 months) 
• Routine Blood and urine tests 
 
During The Study 
• Bone marrow aspirate and biopsy will be done at the end of 4 cycles and 12 cycles of 
treatment, and an additional sample if required to confirm that your disease is in 
remission  
 
Maintenance Phase: 
• Physical Exam, including, weight, vitals and height and assessment of your ability to 
carry out daily activities  
• Routine Blood and urine tests 
• Patient medication diary (monthly) 
 
As of amendment 12;   
You may receive treatment locally, provided the ixazomib can be sent, and provided it is feasible to 
have the evaluations required by the protocol completed remotely or through your local healthcare 
facilities. You will need to return to the enrolling institution every 3rd cycle. 
 
 
6. 
What are the possible risks or discomforts from being in this research 
study? 
 
 
POTENTIAL DISCOMFORTS AND RISKS OF MLN9708 
 
Based on studies of ixazomib it is possible to predict some of the discomforts and risks. 
However, it is possible that ixazomib may cause risks that have not yet been observed in patients.  
The following risks might be seen:   
 
Common risks of Ixazomib (MLN9708) (events occurring greater than 20% of the time) 
• Feeling sick to your stomach (Nausea) 
• Throwing up (Vomiting) 
• Loose Stool (Diarrhea) 
• Constipation 
• Feeling tired or weak 


 
 
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• Decreased number of blood cells (platelets) that help to clot the blood (which could put 
you at increased risk of bleeding (Thrombocytopenia) 
• A low number of white blood cells, which are the infection fighting cells, which could 
put you at risk for infection (Neutropenia) 
• A low number of a particular white blood cell, which is important to the immune system 
(Lymphopenia)  
• Infection including shingles 
• Decrease in red blood cells, which are the oxygen carrying cells which could make you 
feel tired (Anemia)  
• Skin rash  
• Swelling of extremities (arms and/or legs) 
• Numbness and tingling (also known as peripheral neuropathy) 
• Joint pain (arthralgia) 
• Flu like symptoms and other upper respiratory tract infections  
• Lung infections including pneumonia  
• A painful blistery red rash that is confined to one side of the body, similar to chicken pox 
(Herpes zoster)  
 
Less likely risks of Ixazomib (MLN9708) (events occurring less than or equal to 20% of the 
time) 
• Decreased appetite 
• Abdominal pain or distension  
• Back pain  
• Sensation of lightheadedness or vertigo (spinning sensation) (Dizziness) 
• Blood chemical imbalance (Electrolyte imbalance) 
• Excessive or abnormal loss of body fluids (Dehydration) 
 
Rare risks of Ixazomib (MLN9708) (events occurring less than 2-3% of the time) 
• Low or high blood pressure 
• Effects on your nervous system that may cause painful feelings or numbness or tingling 
in hands and feet.  The nerves that control things like your heart rate, gut movement, and 
urinary bladder may be affected 
• Inflammatory response associated with an increase in your white blood cell count, fever, 
and a change in certain protein levels and chemistries in the body  
• Esophageal ulcer 
• Chest pain 
• Abnormal liver tests 
• Decreased weight 
• Fainting episodes 


 
 
Approval Date:  
January 6, 2022 
Not to be used after: February 24, 2022 
 
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• Decreased level of consciousness 
• Tremors 
• Blood clots 
• Inflammation of the lungs 
• Increased blood pressure in the lungs 
• Nosebleeds 
• Muscle weakness 
• Changes in mood 
• Swelling around the eyes 
• Muscle aches 
 
Rare but serious risks of Ixazomib (MLN9708) 
• Life threatening severe skin rash 
• Abnormal heart rhythms 
• Worsening of your heart function (Congestive heart failure) 
• Disorders that could affect the function of your lung that could be serious enough to 
result in death 
• Liver failure 
• Abnormal clotting of the blood in small blood vessels (Thrombotic Thrombocytopenic 
Purpura (TTP)) 
• A complication that may occur if the cancer cells die too quickly that includes 
inappropriate increase or decrease of various natural chemicals in the blood stream, 
called uric acid, phosphorus, potassium, creatinine, and calcium. Severe tumor lysis can 
result in kidney failure and may harm muscle or nerve function (Tumor lysis syndrome) 
•    High creatinine and renal failure. The amount of creatinine (a waste product made by 
your body) in your blood helps your doctor understand how your kidneys are working. 
High creatinine means your kidneys are having trouble working well. Patients who had 
lost body water because of vomiting and/or loose stools have had high levels of creatinine 
indicating that the kidneys were failing to function adequately. In some severe situations, 
less kidney function may require temporary treatment with a machine that supports the 
function of the kidney (dialysis). 
• Blockage of your bowel function 
• Severe rash that can lead to skin peeling and life threatening complications (Stevens 
Johnson syndrome) 
• A condition that can be associated with abnormal neurological function and seizures 
(posterior reversible encephalopathy syndrome; PRES) 
• Inflammation of the spinal cord (transverse myelitis) 


 
 
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January 6, 2022 
Not to be used after: February 24, 2022 
 
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• Progressive multifocal leukoencephalopathy, a rare condition associated with 
inflammation in the brain has been reported, but it is not clear if it is related to the 
medication 
• Acute febrile neutrophilic dermatosis (Sweet’s syndrome), this is a skin condition that 
causes fever and a painful skin rash that appears mostly on the arms, face and neck. 
 
Ixazomib (MLN9708) should not be taken if you have ever had a serious allergic reaction to 
boron or boron containing products. 
 
Dexamethasone 
 
Likely risks of dexamethasone (events occurring greater than 20% of the time) 
• Stomach and throat ulcers or worsening of any ulcers you had before treatment 
• Swelling and pain of the pancreas 
• Weight gain around the stomach 
• Puffiness (especially in the face) 
• Buildup of fluids and a rise in blood pressure 
• Possible rise in your blood sugar 
• Changes in the blood levels of potassium 
• Infection  
 
Less likely risks of dexamethasone (events occurring less than or equal to 20% of the time) 
• Muscle weakness 
• Brittle bones 
• Menstrual changes 
• Itching, and other allergic reactions, some severe   
 
Rare but serious risks of dexamethasone (events occurring less than 2-3% of time) 
• Mood swings 
• Depression 
• Trouble sleeping 
• Changes in personality 
• Seizures 
• Dizziness 
• Patients who are more likely to get heart disease may have heart failure 
 
As with any medication, allergic reactions are a possibility.   
 


 
 
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January 6, 2022 
Not to be used after: February 24, 2022 
 
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The risks of drawing blood include pain, bruising, and rarely, infection at the site of the needle 
stick. 
 
Pregnancy and Birth Control:  
 
RISK TO THE UNBORN CHILD (MEN AND WOMEN) 
Female subjects: We do not know if the study drug Ixazomib will affect mother’s milk or an 
unborn child. Therefore, breast-feeding and pregnant women are not allowed to take part in the 
study.  Due to unknown risks and potential harm to the unborn child/ infant, you should not 
become pregnant or nurse a baby while on this study. 
 
You must have a negative pregnancy test prior to enrolling in the study. 
 
Unless you cannot have children because of surgery or other medical reasons (you had an 
effective tubal ligation, or had the ovaries or the uterus removed; or you are post-menopausal), 
you must use two effective methods of birth control from the time of signing the informed 
consent form, for the entire study drug treatment period, and for 90 days after completing study 
drug treatment.  It is strongly recommended that at least one of these two methods be highly 
effective (see examples below). 
 
Highly effective methods 
Other effective methods (barrier methods) 
Intra-uterine devices (IUD) 
Latex condom with a spermicidal agent 
Hormonal (birth control pills/oral 
contraceptives, injectable 
contraceptives, contraceptive 
patches, or contraceptive implants) 
Diaphragm with spermicide; Cervical cap with 
a spermicide; Sponge with a spermicide 
If one of the highly effective methods cannot be used, using two effective methods at the 
same time are recommended. 
 
You must use birth control methods as directed above, unless you completely avoid having 
heterosexual intercourse.  
 
Male subjects: We do not know if using Ixazomib will affect sperm. Therefore, due to potential 
risk, you should not get your partner pregnant during the study drug treatment period. Even if 
you are surgically sterilized (i.e. have had a vasectomy) you must agree to use an appropriate 
method of barrier contraception (latex condom with a spermicidal agent) during the entire study 
drug treatment period, and for four months after completing study drug treatment. Or, you should 
completely avoid having heterosexual intercourse. 
 
 


 
 
Approval Date:  
January 6, 2022 
Not to be used after: February 24, 2022 
 
IRB#: 13-000414 01 
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Name and Clinic Number 
Highly effective methods 
Other effective methods (barrier 
Vasectomy 
Latex condom with a spermicidal agent 
Diaphragm with spermicide; Cervical cap 
with spermicide; Sponge with spermicide 
If one of the highly effective methods cannot be used, using two effective methods at the 
same time are recommended. 
 
All subjects (male or female): If you or your partner becomes pregnant during this study, you 
must tell the study doctor immediately. The doctor will advise you of the possible risks to your 
unborn child and discuss options for managing the pregnancy with you. For female subjects who 
become pregnant while on this study, the study drug will be stopped immediately and the 
pregnancy will be followed until conclusion. 
 
Risk summary  
 
Many side effects go away shortly after the Ixazomib is stopped, but in some cases side effects 
can be serious, long lasting, or may never go away.  There may be a risk of death. 
 
Some side effects may not be known.  Side effects may range from mild to life-threatening. 
Other drugs may be given to make side effects less serious and less uncomfortable.  Talk to the 
researcher and/or your healthcare provider about side effects and ask any other questions. 
 
Cyclophosphamide 
 
Likely (happening greater than 20% of the time) 
• Feeling sick to the stomach  
• Throwing up 
• Loss of appetite 
• Watery stools 
• Yellowing of the skin 
• Lowering of your blood cell counts which could cause infection or bleeding and you may 
have to have a blood transfusion.  Contact your study doctor right away if you develop 
any signs of infection such as fever, chills, persistent sore throat 
 
Less likely (happening less than or equal to 20% of the time) 
• Escape of the drug from the vein may cause soreness or severe pain and redness in that 
area; pain, redness, and soreness of a vein 
• Temporary hair loss.  Regrowth may have a different color or texture. 


 
 
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January 6, 2022 
Not to be used after: February 24, 2022 
 
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• Bladder irritation.  This can cause pain, blood in the urine, unusual decrease in the 
amount of urine, dark urine, and scarring of the bladder.  If you drink 8 to 10 glasses of 
water a day and empty the bladder frequently, you can avoid this side effect. 
• Damage to the female sex organs.  Women who are still having periods may not have 
them every month or they may stop altogether for a time.  A woman may not be able to 
get pregnant again. 
• Sores in the mouth 
 
Rare but serious (happening less than 3% of the time) 
• Secondary leukemia and/or myelodysplastic syndrome (damage to the bone marrow that 
affects normal blood cell production)  
• Allergic reaction (rapid heartbeat, shortness of breath, wheezing, tightness in the throat) 
• Black/bloody stools 
• Severe stomach/abdominal pain 
• Mental/mood changes 
• Muscle weakness/spasms 
• Swelling of the ankles/feet 
• Sudden or unusual weight gain 
• Headache 
• Dizziness 
• Metallic taste 
• Abnormal liver tests 
• Heart failure has been reported but rarely at the doses given in this study.  This can also 
happen if cyclophosphamide is used in combination with radiation treatment or certain 
other chemotherapy drugs (e.g., doxorubicin).  Seek immediate medical attention if you 
develop chest pain, jaw/left arm pain, trouble breathing, and irregular heartbeat. 
• Scarring of the lungs causing coughing spells and shortness of breath 
 
Side effects may be higher by using other drugs with cyclophosphamide.  Phenobarbital raises 
the effect of cyclophosphamide on your blood cells.  Other drug interactions have been reported.  
If you need anesthesia within 10 days of taking cyclophosphamide, you should let your 
anesthesiologist know about your treatment. 
 
 
 


 
 
Approval Date:  
January 6, 2022 
Not to be used after: February 24, 2022 
 
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7. 
Are there reasons you might leave this research study early? 
 
 
Taking part in this research study is your decision.  You may decide to stop at any time.  You 
should tell the researcher if you decide to stop and you will be advised whether any additional 
tests may need to be done for your safety.  
 
In addition, the researchers, the company supplying drug and funding, or Mayo may stop you 
from taking part in this study at any time: 
• If it is in your best interest,  
• If you do not follow the study rules,  
• If the study is stopped. 
 
 
8. 
What if you are injured from your participation in this research study? 
 
 
Where to get help: 
 
If you think you have suffered a research-related injury, you should promptly notify the Principal 
Investigator listed in the Contact Information at the beginning of this form. Mayo Clinic will 
offer care for research-related injuries, including first aid, emergency treatment and follow-up 
care as needed. 
 
Who will pay for the treatment of research related injuries: 
 
Care for such research-related injuries will be billed in the ordinary manner, to you or your 
insurance.  You will be responsible for all treatment costs not covered by your insurance, 
including deductibles, co-payments and coinsurance.  
 
 
9. 
What are the possible benefits from being in this research study? 
 
 
This study may not make your health better.  If you agree to take part in this study, there may or 
may not be direct medical benefit to you. We hope the information learned from this study will 
benefit other people with multiple amyloidosis in the future. 
 


 
 
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January 6, 2022 
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10. 
What alternative do you have if you choose not to participate in this 
research study? 
 
 
You do not have to be in this study to receive treatment for your condition.  Your other choices 
may include other chemotherapy.  You should talk to the researcher and your regular physician 
about each of your choices before you decide if you will take part in this study. 
 
 
11. 
What tests or procedures will you need to pay for if you take part in this 
research study?  
 
 
You won’t need to pay for tests and procedures which are done just for this research study.  
These tests and procedures are: 
• Study Drug Ixazomib (MLN9708) 
 
However, you and/or your insurance will need to pay for all other tests and procedures that you 
would have as part of your clinical care.  These tests and procedures are: 
• Physical exam, including weight, vital signs, height 
• ECOG performance status (Your ability to carry out daily activities, called your 
“performance status”, will be evaluated) 
• Routine Blood tests 
• Chest x-ray 
• Echocardiogram 
• CT scans if indicated 
• Neurological examination if indicated 
• Bone marrow aspirate and biopsy 
• Pregnancy test (for woman of child bearing potential) 
• Standard of care drugs Cyclophosphamide and Dexamethasone 
 
You will also be responsible for any co-payments and deductibles. Before you take part in this 
study, you should call your insurer to find out if the cost of these tests and/or procedures will be 
covered. You will have to pay for any costs not covered by your insurance.   
 
If you have questions about any costs to you that may result from taking part in the research, 
please speak with the Principal Investigator.  If you wish, arrangements can be made for you to 
speak with someone in Patient Account Services about these costs by calling the telephone 
number provided in the Contact Information section of this form. 


 
 
Approval Date:  
January 6, 2022 
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12. 
Will you be paid for taking part in this research study? 
 
 
You won’t be paid for taking part in this study. 
 
 
13. 
What will happen to your samples? 
 
 
We would like to keep your sample for future research. You can still take part in this current 
study even if you don’t want your sample used for future research. If you agree to give your 
sample, it will be the property of Mayo Clinic. 
 
Other researchers at Mayo Clinic who aren’t involved with this study may ask to use your 
sample for future research. Researchers at other institutions may also ask for a part of your 
sample for future studies. Your sample will be sent to researchers in a coded format, which 
protects your identity. 
 
Some future studies may examine your DNA, which is the genetic information you inherited 
from your parents (genetic testing).  The Principal Investigator may contact you if there are 
findings which may be useful for your health care. You would be given general information on 
the potential risks, benefits, and costs of choosing to learn about the findings.   
 
Please read the following statements and mark your choices: 
 
1.  I permit my sample to be stored and used in future research of Multiple Myeloma at Mayo 
Clinic: 
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 
2.  I permit my sample to be stored and used in future research at Mayo Clinic to learn about, 
prevent, or treat any other health problems: 
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 
3.  I permit Mayo Clinic to give my sample to researchers at other institutions: 
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 
There is a very small chance that some commercial value may result from the use of your 
donated sample.  If that happens, you won’t be offered a share in any profits. 


 
 
Approval Date:  
January 6, 2022 
Not to be used after: February 24, 2022 
 
IRB#: 13-000414 01 
Page 15 of 17 
IRB Doc. Ctrl # 10013.28 
 
 
 
 
 
 
 
Name and Clinic Number 
You may request to have your sample destroyed by writing to the Principal Investigator. The 
address is found in the “Contact Information" section of this consent form. 
 
Because we cannot predict how your sample will be used in the future, we cannot promise that 
samples can be retrieved and destroyed. 
 
 
14. 
How will your privacy and the confidentiality of your records be protected? 
 
 
Mayo Clinic is committed to protecting the confidentiality of information obtained about you in 
connection with this research study. Various methods are used to safeguard confidentiality. Some 
or all of the following may be used in this study: assigning a specific code or registration number 
to each participant’s data and samples, research materials stored in locked areas, password 
protected data stored on a computer.  If the results of the research are made public, information 
that identifies you will not be used. 
 
During this research, information about your health will be collected.  Under Federal law called 
the Privacy Rule, health information is private.  However, there are exceptions to this rule, and 
you should know who may be able to see, use and share your health information for research and 
why they may need to do so.  Information about you and your health cannot be used in this 
research study without your written permission.  If you sign this form, it will provide that 
permission (or “authorization”) to Mayo Clinic.   
 
Health information may be collected about you from: 
• Past, present and future medical records. 
• Research procedures, including research office visits, tests, interviews and 
questionnaires. 
 
Why will this information be used and/or given to others? 
• To do the research. 
• To report the results. 
• To see if the research was done correctly. 
 
If the results of this study are made public, information that identifies you will not be used. 
 
Who may use or share your health information? 
• Mayo Clinic research staff involved in this study.  
• Takeda 
 


 
 
Approval Date:  
January 6, 2022 
Not to be used after: February 24, 2022 
 
IRB#: 13-000414 01 
Page 16 of 17 
IRB Doc. Ctrl # 10013.28 
 
 
 
 
 
 
 
Name and Clinic Number 
With whom may your health information be shared?  
• The Mayo Clinic Institutional Review Board that oversees the research.  
• Other Mayo Clinic physicians involved in your clinical care.  
• Researchers involved in this study at other institutions. 
• Federal and State agencies (such as the Food and Drug Administration, the Department of 
Health and Human Services, the National Institutes of Health and other United States 
agencies) or government agencies in other countries that oversee or review research. 
• The sponsor(s) of this study and the people or groups it hires to help perform this 
research. 
• A group that oversees the data (study information) and safety of this research. 
 
In addition, individuals involved in study oversight and not employed by Mayo Clinic may be 
allowed to review your health information included in past, present, and future medical and/or 
research records. This review may be done on-site at Mayo Clinic or remotely (from an off-site 
location). These records contain information that directly identifies you. However, the 
individuals will not be allowed to record, print, or copy (using paper, digital, photographic or 
other methods), or remove your identifying information from Mayo Clinic. 
 
Is your health information protected after it has been shared with others? 
Mayo Clinic asks anyone who receives your health information from us to protect your privacy; 
however, once your information is shared outside Mayo Clinic, we cannot promise that it will 
remain private and it may no longer be protected by the Privacy Rule. 
 
Your Privacy Rights 
You do not have to sign this form, but if you do not, you cannot take part in this research study. 
 
If you cancel your permission to use or share your health information, your participation in this 
study will end and no more information about you will be collected; however, information 
already collected about you in the study may continue to be used. 
 
If you choose not to take part or if you withdraw from this study, it will not harm your 
relationship with your own doctors or with Mayo Clinic. 
 
You can cancel your permission to use or share your health information at any time by sending a 
letter to the address below: 
 
Mayo Clinic 
Office for Human Research Protection 
ATTN:  Notice of Revocation of Authorization 
200 1st Street SW 
Rochester, MN  55905 


 
 
Approval Date:  
January 6, 2022 
Not to be used after: February 24, 2022 
 
IRB#: 13-000414 01 
Page 17 of 17 
IRB Doc. Ctrl # 10013.28 
 
 
 
 
 
 
 
Name and Clinic Number 
Alternatively, you may cancel your permission by emailing the Mayo Clinic Research Subject 
Advocate at: researchsubjectadvocate@mayo.edu 
 
Please be sure to include in your letter or email: 
• The name of the Principal Investigator, 
• The study IRB number and /or study name, and 
• Your contact information. 
 
Your permission lasts forever, unless you cancel it. 
  
 
ENROLLMENT AND PERMISSION SIGNATURES 
 
 
Your signature documents your permission to take part in this research.  
 
 
 
  
 
 
 
/        /  
 
 
   : 
       AM/PM   
Printed Name  
 
 
 
Date 
 
 
 
Time   
 
 
 
 
_______________________________ 
Signature 
 
 
Person Obtaining Consent  
• I have explained the research study to the participant. 
• I have answered all questions about this research study to the best of my ability. 
 
 
 
  
 
 
 
/        /  
 
 
   : 
       AM/PM   
Printed Name  
 
 
 
Date 
 
 
 
Time           
 
 
_______________________________ 
Signature