Clinical trial NCT02633059
Conditions: Loss of Chromosome 17p Recurrent Plasma Cell Myeloma
Sponsor: Mayo Clinic
Start date: 2015-12-30; Completion date: 2022-11-01
Enrollment: 33 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
This phase I/II trial studies the side effects and best dose of idasanutlin and ixazomib citrate when given together with dexamethasone in treating patients with multiple myeloma that has returned after a period of improvement. Drugs used in chemotherapy, such as idasanutlin 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 idasanutlin, ixazomib citrate, and dexamethasone together may work better in treating patients with multiple myeloma.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the maximum tolerated doses (MTD) of idasanutlin and ixazomib (ixazomib citrate) to be used in combination with dexamethasone in patients with relapsed or refractory multiple myeloma with TP53 (17p) deletion. (Phase I) II. To evaluate the confirmed response rate of ixazomib and idasanutlin used in combination with dexamethasone in patients with relapsed or refractory multiple myeloma with TP53 (17p) deletion. (Phase II)

SECONDARY OBJECTIVES:

I. To describe the toxicities and the confirmed response rate associated with the combination of idasanutlin, ixazomib and dexamethasone. (Phase I) II. To describe the toxicities associated with the combination of idasanutlin, ixazomib and dexamethasone. (Phase II) III. To describe the complete response (CR) and very good partial response (VGPR) rates. (Phase II) IV. To assess progression-free and overall survival. (Phase II)

TERTIARY OBJECTIVES:

I. Assess murine double minute 2 (MDM2) inhibition in bone marrow plasma cells. II. Identify potential biomarkers associated with response. III. To explore the pharmacodynamic effects of idasanutlin.

OUTLINE: This is a phase I, dose-escalation study of idasanutlin and ixazomib citrate followed by a phase II study.

Patients receive ixazomib citrate orally (PO) on days 1, 8, and 15 and idasanutlin PO once daily (QD) on days 1-5 every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive dexamethasone PO on days 1, 8, 15, and 22 every 28 days for 12 courses at the discretion of the treating physician.

After completion of study treatment, patients are followed up for 30 days, every 3 months, and then every 6 months.

Arms: arm 1: Patients receive ixazomib citrate PO on days 1, 8, and 15 and idasanutlin PO QD on days 1-5 every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive dexamethasone PO on days 1, 8, 15, and 22 every 28 days for 12 courses at the discretion of the treating physician.
Interventions: intervention 1: Dexamethasone intervention 2: Idasanutlin intervention 3: Ixazomib Citrate intervention 4: Laboratory Biomarker Analysis intervention 5: Pharmacological Study
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Given PO intervention 4: Correlative studies intervention 5: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 




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Table of Contents 
Phase 1 / 2 trial of Idasanutlin in combination with Ixazomib and dexamethasone  in patients 
with 17p deleted, relapsed multiple myeloma ................................................................................ 1 
Protocol Resources.......................................................................................................................... 2 
Table of Contents ............................................................................................................................ 3 
Schema ............................................................................................................................................ 4 
1.0 
Background ...................................................................................................................... 5 
2.0 
Objectives ....................................................................................................................... 27 
3.0 
Patient Eligibility ............................................................................................................ 28 
4.0 
Study Calendar ............................................................................................................... 31 
5.0 
Grouping Factor: ............................................................................................................ 33 
6.0 
Registration Procedures.................................................................................................. 33 
7.0 
Protocol Treatment ......................................................................................................... 35 
8.0 
Dosage Modification Based on Adverse Events ............................................................ 38 
9.0 
Ancillary Treatment/Supportive Care ............................................................................ 44 
10.0 
Adverse Event (AE) Reporting and Monitoring ......................................................... 47 
11.0 
Treatment Evaluation ................................................................................................. 62 
12.0 
Descriptive Factors ..................................................................................................... 66 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ........................................... 66 
14.0 
Biospecimens .............................................................................................................. 68 
15.0 
Drug Information ........................................................................................................ 71 
17.0 
Pathology Considerations/Tissue Biospecimens ........................................................ 87 
18.0 
Records and Data Collection Procedures ................................................................... 87 
19.0 
Budget ......................................................................................................................... 88 
20.0 
References .................................................................................................................. 89 
Appendix I ECOG Performance Status ..................................................................................... 92 
Appendix II 
Patient Medication Diary .................................................................................... 93 
Appendix III 
Drug Classification Guide ................................................................................... 94 
Appendix IV 
Cockcroft-Gault Equation ................................................................................... 96 
Appendix V 
MC1582 Model Consent ..................................................................................... 97 




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1.0 
Background 
1.1 Multiple Myeloma: Multiple myeloma (MM) is an incurable malignancy arising from post 
germinal center, terminally differentiated plasma cells, characterized by an excess of 
monotypic plasma cells in the bone marrow, resulting in elevated levels of monoclonal 
immunoglobulins (Ig) in the serum and/or urine. Common clinical sequelae include lytic bone 
lesions, fractures, myelosuppression, and renal failure. In the United States of America 
(USA), the estimated annual diagnosed incidence is 22,350, with approximately 100,000 
prevalent cases.(Siegel, Naishadham et al. 2013) In Europe, the estimated annual diagnosed 
incidence is 21,611 with approximately 54,536 prevalent cases.(1998) Multiple myeloma 
accounts for 10% of all hematologic malignancies and 1% of all malignancies. Advances in 
high-dose chemotherapy and stem cell transplantation have improved overall survival and 
event-free disease periods in patients with MM, but relapses are inevitable.(Kumar, Lee et al. 
2012, Kumar, Dispenzieri et al. 2013) New therapeutic agents, such as bortezomib and 
thalidomide analogues, have shown promising clinical benefit in patients with relapsed or 
refractory disease. Current treatments include combination chemotherapy with regimens 
using melphalan (Alkeran®), bortezomib (Velcade®), thalidomide (Thalomid®), and 
lenalidomide (Revlimid®) with and without corticosteroids.(Mikhael, Dingli et al. 2013) 
Younger patients are consolidated with high-dose therapy (ablative chemotherapy or 
radiation) with autologous stem cell transplantation (ASCT). Despite these therapeutic 
advances, MM remains essentially incurable and is associated with high morbidity and 
mortality.(Palumbo, Bringhen et al. 2006) Multiple myeloma (MM) is a heterogeneous 
disease with diverse outcomes dictated in large part by the presence of various genetic 
abnormalities. Genetic abnormalities are seen in the plasma cells in nearly all patients with 
myeloma, especially when assessed with interphase FISH.(Avet-Loiseau, Attal et al. 2007, 
Fonseca, Bergsagel et al. 2009) The abnormalities broadly consist of translocations involving 
the immunoglobulin heavy chain locus on chromosome 14 or trisomies of one or more odd 
numbered chromosomes, or a combination of the two.(Kumar, Fonseca et al. 2012) Presence 
of certain genetic abnormalities are associated with a dismal outcome; abnormalities that 
denote high-risk myeloma. Among these, presence of p53 abnormality in particular is 
associated with a poor survival, with median overall survival of 3 years or less.(Lopez-
Anglada, Gutierrez et al. 2010, Kumar, Fonseca et al. 2012) These patients respond well to 
initial therapy, but rapidly become refractory to the available therapies and relapse. Studies 
have suggested that myeloma cells are genomically unstable, and loss of p53 may signal 
heightened instability. Given the poor outcome seen in these patients even with the most 
effective regimens, it is imperative we design new approaches to treat these patients. 
 
1.2 17p deletion in multiple myeloma: Survival of patients with multiple myeloma (MM) has 
nearly doubled in the previous decade, but nearly a quarter of patients have an aggressive 
course with median survival of less than 3 years.(Kumar, Rajkumar et al. 2008) Genetic 
abnormalities are the major determinants of outcome in myeloma and can be broadly grouped 
into trisomies, translocations involving heavy chain locus on chromosome 14, and 
monosomies or deletions involving various chromosomes(Avet-Loiseau, Attal et al. 2007, 
Kumar, Mikhael et al. 2009, Kumar, Fonseca et al. 2012) Trisomies typically involve the odd 
numbered chromosomes and are associated with good outcome.(Chng, Van Wier et al. 2005) 
There are five recurrent translocations that can affect the IgH locus resulting in activation of 
different oncogenes. Among these t(4;14), t(14;16) and t(14;20) are associated with shortened 
survival.(Bergsagel and Kuehl 2005) Finally, partial deletions or monosomies affecting 
chromosomes 1, 13, 14, 16 and 17 have been reported. In particular, loss of the short arm of 
chromosome (17p-) or its monosomy results in loss of the TP53 gene.(Chng, Price-Troska et 
al. 2007) This abnormality is seen in approximately 10% of patients at diagnosis and 10-15% 


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of patients at relapse and results in short response duration to therapy, rapidly becoming 
resistant to all available therapies and succumbing to the disease within the first 2-3 years 
after diagnosis.(Neri, Baldini et al. 1993, Drach, Ackermann et al. 1998, Avet-Loiseau, Li et 
al. 1999, Chang, Qi et al. 2005, Gertz, Lacy et al. 2005, Chng, Price-Troska et al. 2007, 
Tiedemann, Gonzalez-Paz et al. 2008, Xiong, Wu et al. 2008) Abnormalities of the TP53 
gene have been associated with poor outcome in almost all cancers studied, including 
hematological cancers and solid tumors. The TP53 gene is often referred to as the ‘guardian 
of the genome’, given its crucial role in induction of apoptosis in cells in the presence of 
DNA damage. Following DNA damage, TP53 regulates key processes, including DNA 
repair, cell-cycle arrest, senescence and apoptosis. This serves to suppress replication and 
propagation of the cells with the damaged DNA, thus reducing the risk of cancer. In the 
absence of normal TP53 function, many cancer therapies do not work well given the inability 
to induce apoptosis through DNA damage mechanisms. In the majority of tumors, loss of 
TP53 function is a result of a mutated TP53 gene. In sharp contrast, TP53 abnormalities in 
MM appear to be related primarily to loss of the gene through an interstitial deletion or 
monosomy of chromosome 17.(Chng, Price-Troska et al. 2007, Xiong, Wu et al. 2008) The 
lack of mutations involving the TP53 gene in MM, unlike other cancers, opens up new 
therapeutic potential in terms of modulation of TP53 gene function. In normal cells, p53 
levels are regulated by MDM2, a RING domain protein, through a negative feedback loop. 
When nuclear p53 levels are elevated, transcription of the MDM2 gene occurs leading to 
increased cellular levels of mdm2 protein, which in turn binds to p53 and blocks its 
transactivation domain. MDM2 also has a p53- specific E3 ubiquitin ligase activity that leads 
to ubiquitin-dependent degradation of p53. Therefore, blocking the p53-MDM2 interaction 
can enhance levels of p53 in the presence of a functional p53 gene and particularly in the 
setting of myeloma, may be able to compensate for the loss of one of the alleles. Pre-clinical 
studies with nutlin-class drugs have demonstrated potent in vitro activity for this mechanism 
in myeloma. (Stuhmer, Chatterjee et al. 2005, Stuhmer and Bargou 2006, Saha, Jiang et al. 
2010, Saha, Jiang et al. 2010) 
 
1.3 Proteasome inhibitors and 17p deletion: Bortezomib as part of induction as well as 
maintenance therapy has been associated with improved outcomes in patients with TP53 
deletion. In a series of 354 MM patients treated within the HOVON-65/GMMG-HD4 trial, 
Neben et al analyzed the effect of a bortezomib-based treatment before and after autologous 
stem cell transplantation compared with standard treatment without bortezomib. Patients with 
del(17p13) had a significant benefit with the bortezomib-containing treatment: the median 
PFS was 12.0 months without bortezomib compared to 26.2 months (P = .024) with 
bortezomib; the 3 year-OS was 17% and 69%, respectively (P = .028). 
 
1.4 Ixazomib: MLN9708, 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. In water or aqueous systems, MLN9708 
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 MLN9708. 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 


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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. 
 
Please refer to the latest version of the Ixazomib IB for further details. 
 
Nonclinical Pharmacology: MLN2238 refers to the biologically active, boronic acid form of 
the drug substance, ixazomib citrate (MLN9708). Ixazomib citrate 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 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 


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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). 
 
MLN2238 is neither an inhibitor of CYP isozymes 1A2, 2C9, 2C19, 2D6, or 3A4 (IC50 
>30μM, with an estimated inhibition dissociation constant [Ki] >15μM), 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. 
 


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Ixazomib Safety Pharmacology: In exploratory safety pharmacology studies, MLN2238 was 
a weak inhibitor of the cloned cardiac potassium (K+) human ether à-go-go 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. 
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 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. 


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• 
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: Ixazomib is a small molecule peptide boronic acid. 
Ixazomib is the first investigational proteasome inhibitor with substantial oral bioavailability 
in patients with multiple 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. 
Ongoing studies continue to investigate both single-agent ixazomib and ixazomib in 
combination with standard treatments. Based on encouraging preliminary data observed in 
patients with MM requiring systemic treatment, two phase 3 trials in newly diagnosed MM 
(NDMM) (C16014) and RRMM (C16010) patient populations are currently evaluating 
ixazomib in combination with lenalidomide (Revlimid®) and dexamethasone (RevDex) 
versus placebo/RevDex. Both trials are combining ixazomib at a weekly dose of 4.0 mg on 
Days 1, 8, and 15 in a 28-day cycle to a standard dose of lenalidomide with a weekly 
dexamethasone dose of 40 mg. In addition, ongoing clinical pharmacology studies include 
evaluation of drug-drug interactions with ketoconazole and rifampin, effect of food, and oral 
bioavailability. Studies evaluating the safety and pharmacokinetic (PK) of ixazomib alone (in 
Japanese patients) and in combination with lenalidomide and dexamethasone in Asian adult 
patients (including Japanese patients) with a diagnosis of NDMM are ongoing. 
 
As of 27 March 2013, preliminary clinical data are available for a total of 653 patients across 
13 studies. The emerging safety profile indicates that ixazomib is generally well tolerated. 
The adverse events (AEs) are consistent with the class-based effects of proteasome inhibition 
and are similar to what has been previously reported with bortezomib though the severity of 
some, for example peripheral neuropathy, is less. While some of these potential toxicities 
may be severe, they can be managed by clinical monitoring and standard medical 
intervention, or, as needed, dose modification or discontinuation. 
 
Fatigue was the most common AE reported among 384 patients treated in the oral (PO) 
studies (47%). Other common AEs reported in the pooled intravenous (IV) and PO safety 
populations include nausea, thrombocytopenia, diarrhea, and vomiting. Rash is also a 
commonly reported treatment-emergent event; however, there is some variety in its 
characterization and causality resulting in different preferred terms to describe it. A high-
level term outline of rash events includes rashes, eruptions and exanthems NEC; pruritus 
NEC; erythemas; papulosquamous conditions; and exfoliative conditions. The dose escalation 
phases of most trials reported in the IB have now completed enrollment, and gastrointestinal 
(GI) symptoms were the common dose-limiting toxicities (DLTs) when the use of 


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prophylactic anti-emetics was not permitted per protocol. In the expansion cohorts or phase 2 
cohorts (per each study), the incidence and severity of GI symptoms was mitigated by the use 
of the lower maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) (per each 
study) and standard clinical usage of anti-emetics and/or antidiarrheal medications as deemed 
appropriate. Prophylactic use of anti-emetics has not been required as with other agents but 
has been used according to standard practice and are effective. 
 
The most frequent (at least 20%) treatment-emergent adverse events (TEAEs) reported with 
the PO formulation pooled from single-agent studies (n=201) irrespective of causality to 
ixazomib, include nausea (53%), fatigue (51%), diarrhea (44%), thrombocytopenia (34%), 
vomiting (38%), decreased appetite (32%), fever (21%), and anemia (21%). The most 
frequent (at least 20%) TEAEs reported with the PO formulation pooled from combination 
trials (irrespective of the combination) (n=173), irrespective of causality to ixazomib, include 
diarrhea (47%), fatigue (44%), nausea (38%), peripheral edema (35%), constipation (33%), 
insomnia (29%), thrombocytopenia (28%), anemia (26%), vomiting (26%), neutropenia 
(25%), back pain (24%), pyrexia (23%), fever (20%), cough (20%), hypokalemia (20%), 
neutropenia (20%), and upper respiratory tract infection (20%). Overall rash of all grades is 
reported in approximately 50% of patients and is more common when ixazomib is given in 
combination with lenalidomide, where rash is an overlapping toxicity. Additional detailed 
information regarding the clinical experience of ixazomib may be found in the IB, including 
information on the IV formulation. 
 
Pharmacokinetics and Drug Metabolism: Clinical IV and PO PK data show that ixazomib 
citrate (measured as the biologically active boronic acid form of ixazomib [MLN2238]) has 
multi-exponential disposition with a rapid initial phase that is largely over by 4 hours. Oral 
ixazomib citrate is rapidly absorbed with a median single-dose first time of occurrence of 
maximum (peak) concentration (Tmax) of approximately 0.5 to 2.0 hours and a terminal 
disposition half-life (t1/2) after multiple dosing of approximately 5 to 7 days. 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.(Gupta, Saleh et al. 
2011, Gupta, Saleh et al. 2012) 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. Please refer to the current ixazomib IB and Safety 
Management Attachment (SMA) for information on the PK for IV doses of ixazomib. 
 
Clinical Study C16009 (Arm 1) with ketoconazole, a strong CYP3A4 inhibitor, showed a 2-
fold increase in area under the plasma concentration versus time curve (AUC) in the presence 
of ketoconazole. This resulted in the continued exclusion of strong CYP3A4 inhibitors in 
ongoing/planned clinical studies. 
 
Clinical Trial Experience Using the Oral Formulation of Ixazomib: As of 27 March 2013, a 
total of 507 patients with differing malignancies (multiple myeloma, AL amyloidosis, 
nonhematologic cancers, and lymphoma) have been treated in studies evaluating the oral 
ixazomib formulation. These patients have been treated with different doses of ixazomib 
either as a single-agent treatment (in 201 patients) or in combination with currently clinically 
available treatments (in 306 patients). Information regarding the ongoing studies, patient 
populations, and doses investigated is included in Table 1-1. 
 
 


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Protocol version date: 17Mar2020 
Table 1-1 
Clinical Studies of Oral Ixazomib 
Trial/ 
Population 
Description 
Doses Investigated 
C16003 
RRMM 
N = 60 
PO, TW, single agent 
0.24-2.23 mg/m2 TW 
MTD: 2.0 mg/m2 
DLT: rash, thrombocytopenia 
Closed to enrollment 
C16004 
RRMM 
N = 60 
PO, W, single agent 
0.24-3.95 mg/m2 W 
MTD: 2.97 mg/m2 
DLT: rash, nausea, vomiting, diarrhea 
Closed to enrollment 
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 
RP2Da: 4.0 mg fixed (switched to fixed dosing in 
phase 2, equivalent to 2.23mg/m2) 
Closed to enrollment 
C16006 
NDMM 
N = 20 
PO, TW (Arm A- 42 day cycle) and 
W (Arm B- 28 day cycle), 
combination with Melphalan and 
Prednisone 
Arm Aa: 3-3.7-mg fixed dose TW 
DLT: rash, thrombocytopenia, subileus 
Arm Ba: 3-5.5-mg fixed dose, W 
DLT: Esophageal ulcer nausea, vomiting, 
hematemesis, thrombocytopenia, ileus, 
neurogenic bladder 
MTD = 3.0 mg 
C16007 
RRAL 
N = 27 
PO, W, single agent 
4-5.5-mg fixed dosea W 
DLT: thrombocytopenia, diarrhea, dyspnea, acute 
rise in creatinine, cardiac arrest  
MTD: 4.0 mg W 
C16008 
NDMM 
N = 64 
PO, TW, combination with LenDex 
21-day cycle 
3.0-3.7-mg fixed dosea W 
MTD: 3.0 mg 
Closed to enrollment 
C16009 
Solid tumors, 
Lymphomas 
N = 54 
PO, W, single agent 
5.5-mg fixed dosea W 
C16010 
RRMM 
N = 200 
PO, W, with LenDex versus placebo-
LenDex 
4.0 mg W 
C16011 
RRAL 
N = 4 
PO, W, with Dex versus physician’s 
choice of a Dex-based regimen 
4.0 mg W 
C16013 
RRMM 
N = 9 
PO, W, with LenDex 
4.0 mg W 


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Protocol version date: 17Mar2020 
Table 1-1 
Clinical Studies of Oral Ixazomib 
Trial/ 
Population 
Description 
Doses Investigated 
C16014 
Symptomatic MM 
N=701 
PO, combination with LenDex 
ixazomib 4.0 mg or matching placebo on Days 1, 
8, and 15, plus Len 25 mg on Days 1-21 (10 mg if 
low creatinine clearance, with escalation to 15 mg 
if tolerated) and Dex 40 mg (or 20 mg if 
>75 years old) on Days 1, 8, 15, and 22 
C16015 
Symptomatic MM 
with normal renal 
function or severe 
renal impairment 
N=28 
PO, combination with Dex 
Part A: ixazomib 3.0 mg on Day 1 
Part B: ixazomib 4.0 mg on Days 1, 8, and 15, 
plus Dex 40 mg (or 20 mg if >75 years old) on 
Days 1, 8, 15 and 22 of a 28-day cycle 
C16017 
RR follicular 
lymphoma 
N=58 
PO, W 
4.0, 5.3, and 7.0 mg, W 
Treatment at RP2D once determined. 
C16018 
Advanced solid 
tumors or 
hematologic 
malignancies with 
varying degrees of 
liver dysfunction 
N=45 
Part A: PO, Day 1 of 15-day cycle 
Part B: PO, W 
1.5 mg (severe hepatic impairment), 2.3 mg 
(moderate hepatic impairment), or 4.0 mg 
(normal hepatic function) 
TB-MC010034 
RRMM 
N = 10 
PO, W 
4.0 mg, W 
Single agent: 4.0 mg 
Combination with Rd 
Abbreviations: RRAL = Relapsed and/or refractory Primary systemic light chain (AL) amyloidosis; BSA = body 
surface area; Dex=dexamethasone; DLT = dose-limiting toxicity; IV = intravenously; LenDex = lenalidomide 
plus dexamethasone; MTD = maximum tolerated dose; NDMM = newly diagnosed multiple myeloma; PO = 
orally; RR= relapsed and/or refractory; RRAL= relapsed and/or refractory systemic light chain amyloidosis 
RRMM = relapsed and/or refractory multiple myeloma; TBD = to be determined; TW = twice weekly; W = 
weekly; RP2D= recommended phase 2 dose. 
Note that blinded data from pivotal Studies C16010 and C16011 are not included. 
a Approximate 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 
 
1.5 Potential Risks of Ixazomib:  
The emerging safety profile indicates that ixazomib is generally well tolerated. The adverse 
events (AEs) are consistent with the class-based effects of proteasome inhibition and are 
similar to what has been previously reported with bortezomib, though the severity of some, 
for example peripheral neuropathy, is less. While some of these potential toxicities may be 
severe, they can be managed by clinical monitoring and standard medical intervention, or, as 
needed, dose modification or discontinuation. In the four ongoing studies (C16003, C16004, 
C16007, and C16009) investigating single-agent oral ixazomib in patients with differing 
malignancies (multiple myeloma, AL amyloidosis, non-hematologic cancers, and 
lymphoma), a total of 201 patients have been treated as of 27 March 2013. These patients 


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Protocol version date: 17Mar2020 
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) are shown in 
Table 1-2. 
Table 1-2 
Most Common (At Least 10% of Total) Treatment-Emergent Adverse Events 
in Oral Single-Agent Studies 
Primary System Organ Class 
Preferred Term 
Oral Single Agent 
Total n=201 (n%) 
Subjects with at Least One Adverse Event 
197 (98) 
Gastrointestinal disorders 
160 (80) 
 Nausea 
106 (53) 
 Diarrhea 
88 (44) 
 Vomiting 
77 (38) 
 Constipation 
46 (23) 
 Abdominal pain 
33 (16) 
General disorders and administration site 
conditions 
151 (75) 
 Fatigue 
103 (51) 
 Pyrexia 
51 (25) 
 Edema peripheral 
27 (13) 
 Asthenia 
31 (15) 
Nervous system disorders 
92 (46) 
 Headache 
29 (14) 
 Dizziness 
26 (13) 
 Neuropathy peripheral 
21 (10) 
Metabolism and nutrition disorders 
107 (53) 
 Decreased appetite 
64 (32) 
 Dehydration 
37 (18) 
Blood and lymphatic system disorders 
98 (49) 
 Thrombocytopenia 
68 (34) 
 Anemia 
42 (21) 
 Neutropenia 
29 (14) 
 Lymphopenia 
20 (10) 
Skin and subcutaneous tissue disorders 
90 (45) 
 Rash maculara 
23 (11) 
Musculoskeletal and connective tissue disorders 93 (46) 
 Back pain 
24 (12) 
 Arthralgia 
28 (14) 
Respiratory, thoracic and mediastinal disorders 
78 (39) 
 Cough 
28 (14) 
 Dyspnea 
30 (15) 
Infections and infestations 
89 (44) 
 Upper respiratory tract infection 
31 (15) 


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Protocol version date: 17Mar2020 
Table 1-2 
Most Common (At Least 10% of Total) Treatment-Emergent Adverse Events 
in Oral Single-Agent Studies 
Primary System Organ Class 
Preferred Term 
Oral Single Agent 
Total n=201 (n%) 
Source: Ixazomib Investigator’s Brochure Edition 7 
Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities, version 15.0 
Subject Incidence: A subject counts once for each preferred term. Percentages use the 
number of treated subjects as the denominator. 
a 
Note that rash maculopapular and rash macular represent the two most common terms 
used to describe rash. 
 
As of 27 March 2013, there are 5 studies actively enrolling patients with multiple myeloma to investigate 
oral ixazomib in combination with standard combination regimens. The most frequent (at least 10%) AEs 
occurring in the pooled safety population from Studies C16005, C16006, C16008, and C16013 are shown 
for all grades (Table 1-3). Note that in combination trials, “related” is defined as related to any study drug 
in the combination regimen. 
 
Table 1-3 
Most Common (At Least 10% of Total) Treatment-Emergent Adverse Events 
in Oral Combination Studies 
Primary System Organ Class 
Preferred Term 
Total Oral Combo Agent 
(5/6/8/13) 
n = 173 (n%) 
Subjects with at Least One Adverse Event 
163 (94) 
Gastrointestinal disorders 
139 (80) 
 Nausea 
65 (38) 
 Diarrhea 
81 (47) 
 Vomiting 
51 (29) 
 Constipation 
57 (33) 
General disorders and administration site 
conditions 
132 (76) 
 Fatigue 
76 (44) 
 Pyrexia 
39 (23) 
 Edema peripheral 
61 (35) 
 Asthenia 
20 (12) 
Nervous system disorders 
115 (66) 


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Protocol version date: 17Mar2020 
Table 1-3 
Most Common (At Least 10% of Total) Treatment-Emergent Adverse Events 
in Oral Combination Studies 
Primary System Organ Class 
Preferred Term 
Total Oral Combo Agent 
(5/6/8/13) 
n = 173 (n%) 
 Headache 
28 (16) 
 Dizziness 
34 (20) 
 Neuropathy peripheral 
45 (26) 
Metabolism and nutrition disorders 
91 (53) 
 Decreased appetite 
25 (14) 
 Hypokalemia 
34 (20) 
Blood and lymphatic system disorders 
88 (51) 
 Thrombocytopenia 
49 (28) 
 Anemia 
45 (26) 
 Neutropenia 
43 (25) 
 Lymphopenia 
20 (12) 
Skin and subcutaneous tissue disorders 
102 (59) 
 Rash maculopapular 
29 (17) 
 Rash maculara 
22 (13) 
Musculoskeletal and connective tissue 
disorders 
99 (57) 
 Back pain 
42 (24) 
 Pain in extremity 
31 (18) 
 Arthralgia 
22 (13) 
Respiratory, thoracic and mediastinal 
disorders 
80 (46) 
 Cough 
36 (21) 
 Dyspnea 
26 (15) 


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Protocol version date: 17Mar2020 
Table 1-3 
Most Common (At Least 10% of Total) Treatment-Emergent Adverse Events 
in Oral Combination Studies 
Primary System Organ Class 
Preferred Term 
Total Oral Combo Agent 
(5/6/8/13) 
n = 173 (n%) 
Infections and infestations 
92 (53) 
 Upper respiratory tract infection 
35 (20) 
Psychiatric disorders 
73 (42) 
 Insomnia 
50 (29) 
Source: Ixazomib Investigator’s Brochure Edition 7 
Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities, version 15.0 
Subject Incidence: A subject counts once for each preferred term. Percentages use the 
number of treated subjects as the denominator.  
Data from ongoing blinded pivotal trials (C16010) are not included. 
a 
Note that rash maculopapular and rash macular represent the two most common terms 
used to describe rash 
 
The clinical experience with ixazomib also shows early signs of antitumor activity as 
evidenced by at least a 50% reduction in disease burden in some patients and prolonged 
disease stabilization in others across all ongoing trials. The antitumor activity has been seen 
with single-agent ixazomib, when combined with established therapies, and across the 
malignancies studied (advanced solid tumors, non-Hodgkin’s disease, Hodgkin’s disease, 
relapsed and/or refractory multiple myeloma, relapsed or refractory systemic light chain 
amyloidosis, and newly diagnosed multiple myeloma) to date.(Kumar, Bensinger et al. 2014, 
Kumar, Bensinger et al. 2014, Kumar, Berdeja et al. 2014, Richardson, Baz et al. 2014) 
 
1.6 Idasanutlin (RO5503781): Idasanutlin is a potent and selective inhibitor of the p53-MDM2 
interaction that activates the p53 pathway and induces cell cycle arrest and/or apoptosis in a 
variety of tumor types expressing wild-type p53 in vitro and in vivo. It binds MDM2 in the 
p53 pocket with a high affinity (KD=11 nM) leading to stabilization and accumulation of p53 
and consequent signaling. It blocks cell cycle progression in G1 and G2 leading to inhibition 
of cancer cell growth. It has a 30-fold selective toxicity for wild-type vs. mutant p53 cells. In 
a recent Phase 1 trial, treatment with idasanutlin was well tolerated and efficacy was seen in 
some patients with acute myeloid leukemia. Additionally, preclinical models have established 
that the activity of idasanutlin may be potentiated when combined with rational therapeutic 
partners to improve efficacy, lending credence to such combinational regimens displaying 
synergistic anti-cancer effects. 
 
Non-clinical Pharmacology: The pharmacology, pharmacokinetics, and toxicology of 
idasanutlin have been investigated in several nonclinical studies. In cell-free assays, 
idasanutlin binds to MDM2 protein with high affinity (dissociation constant [KD] = 5.7 nM) 
and inhibits MDM2-p53 binding with drug concentration, which causes IC50 of 6.6 ± 1.0 nM. 
Exposure of cultured cancer cells to the compound leads to a dose-dependent accumulation of 
p53 protein and activation of its transcriptional targets and the p53 pathway. As a result, 
cancer cells undergo a cell cycle block in the G1 and G2 phase followed by apoptosis. In 


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vivo, idasanutlin has shown antitumor activity at nontoxic doses against an established 
osteosarcoma xenograft model. These nonclinical pharmacology results support further 
evaluation of idasanutlin in clinical studies. 
 
Nonclinical Pharmacokinetics and Metabolism: Single-dose pharmacokinetics of 
idasanutlin were evaluated in mice, rats, dogs, and monkeys following intravenous (IV) and 
oral dosing. High exposures were achieved in all nonclinical species after oral administration 
and high oral bioavailability was observed in rodents (low in non-rodents). Multiple-dose 
pharmacokinetics of idasanutlin were studied during general toxicology studies in Han Wistar 
rats and cynomolgus monkeys following oral dosing. Exposure increased with increasing 
dose level and no gender difference was apparent. In rats, there was generally no 
accumulation or loss of exposure after multiple days of dosing. However, after repeat dosing 
of idasanutlin in monkeys, decreases in exposure were apparent at all dose levels, which 
correlates to monkey-specific CYP3A induction in intestine and liver. 
 
In vitro plasma protein binding was high (99.99%) and similar across species (mouse, rat, 
dog, monkey, and human). Tissue distribution studies in rats showed that idasanutlin was 
widely distributed and the highest concentration was observed about 4 hours post dose in 
intestine, liver, adrenal gland, colon, cecum, kidney cortex, and gastric mucosa. Low 
metabolism occurred in rat, monkey, and human liver microsomal and hepatocyte 
incubations. Based on in vitro results, both rats and monkeys produced the same metabolites 
as humans, which supported the choice of these species for toxicological evaluation. In rats in 
vivo, [14C]-idasanutlin and its related metabolites were mainly excreted hepatically through 
bile with minimal renal elimination. Results from in vivo metabolic profiles and metabolite 
identification of idasanutlin in human plasma and urine showed that 1) glucuronidation of 
idasanutlin seems to play a minor role in terms of human plasma exposure; 2) rat and 
cynomolgus monkey metabolic patterns together cover the human plasma metabolite pattern; 
and 3) idasanutlin is not excreted through urine. 
 
At therapeutic dose levels, idasanutlin has the potential for drug-drug interactions as a 
perpetrator with CYP2C8 substrates. Idasanutlin is metabolized by multiple metabolic 
enzymes, mainly by CYP2C8, CYP3A4/5, and UDP-glucuronosyltransferase (UGT). Strong 
inhibitors and/or inducers of these enzymes may affect exposure of idasanutlin. 
 
Toxicology and Safety Pharmacology 
Pivotal repeat-dose cycling studies in rats and monkeys that consisted of two dosing cycles of 
10 days duration with an intervening drug holiday of 18 days, followed by a recovery period, 
confirmed that idasanutlin produced target organ toxicity that was expected for a compound 
that disrupts the cell cycle. Safety findings identified in the toxicology studies at exposures 
that approximate the anticipated therapeutic range are considered clinically manageable (e.g., 
diarrhea), monitorable (e.g., suppression of blood cell components) and/or reversible (e.g., 
body and organ weight changes and diarrhea). In the Good Laboratory Practice (GLP) 
cycling studies, oral administration of idasanutlin to rats and monkeys resulted in 
moribundity; diarrhea (monkeys only); decreased body weight and/or body weight gain (rats 
only); decreased food consumption; sporadic increases in serum liver function tests (rats 
only); and target organ toxicities, including bone marrow hypocellularity, reduced leukocytes, 
erythrocytes, and/or platelets, decreased thymus or spleen weights, and lymphoid depletion in 
the thymus, spleen, mesenteric lymph nodes, and/or gut-associated lymphoid tissue (GALT). 
Moribundity in monkeys occurred at doses ≥ 60 mg/kg/day. In rats, moribundity and 
premature death were noted at doses ≥ 500 mg/kg/day. In general, treatment-related findings 
either fully or partially resolved during the recovery period. The maximum tolerated doses 


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Protocol version date: 17Mar2020 
(MTD) for two cycles of treatment with idasanutlin were considered to be 30 and 300 
mg/kg/day in cynomolgus monkeys and Wistar rats, respectively. No biologically relevant 
adverse effects were observed in the CNS or pulmonary system. Cardiovascular effects were 
limited to a reversible increase in heart rate in male monkeys at doses above the MTD. A 
GLP human ether-à-go-go-related gene (hERG) assay conducted at physiological temperature 
showed an IC20 of ≥ 1.8 μM, but was of limited value because of insolubility of idasanutlin. 
Importantly, there was no effect on the corrected QT interval (QTc) in the pivotal monkey 
study at doses that exceeded the MTD. Based on ultraviolet A (UVA)/ultraviolet B (UVB) 
absorption spectrum, idasanutlin demonstrates a potential for phototoxicity. Therefore, an in 
vivo phototoxicity study was conducted in Long Evans rats. Idasanutlin did not induce a 
phototoxic skin reaction at any dose, which indicated that there is little to no risk of 
phototoxicity in cancer patients. 
 
RO0478485 (4-amino-3-methoxy-benzoic acid) is a potential impurity and degradation 
product of idasanutlin that is formed by hydrolysis of the amide bond. RO0478485 induced a 
weak but dose-related increase in the number of revertant colonies after metabolic activation. 
In order to reduce the amount of this impurity to levels as low as reasonably possible, 
adjustments to the drug substance and drug product process and different storage conditions 
are under evaluation. 
 
CLINICAL INFORMATION 
Two Phase I clinical studies of idasanutlin are complete in patients with solid tumors (Studies 
NP27872 and NP28902) and one Phase I/Ib study is currently ongoing in patients with AML 
(Study NP28679).  
 


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Protocol version date: 17Mar2020 
 
Table 1-4 
Completed, Ongoing, and Planned Idasanutlin Studies 
Protocol 
No. 
Phase, Design 
Patient Population, No. of 
Patients  
Monotherapy/ 
Combination 
Therapy 
Formulation 
Current Status 
NP28679 
Phase I/Ib, Dose-escalation of single 
agent (Part 1) and in combination with 
cytarabine (Part 2) or in combination 
with cytarabine and anthracycline 
(Part 3), and assessment of PK and 
safety of optimized SDP formulation 
(Part 4) 
AML, N = 105 a 
(Part 1, N = 20  
Part 1 extension, N = 9 
Part 2, N = 23  
Part 2 extension, N = 38 
Part 3, N = 0 
Part 4, N = 15) 
Idasanutlin 
monotherapy and 
combination 
therapy with 
cytarabine -
containing 
regimens 
Parts 1, 2, 
1 extension, 
2 extension =
 MBP 
 
Part 4 = SDP 
Part 1 and Part 2 dose 
escalation complete; 
Part 1 extension 
discontinued b, Part 2 
extension complete, 
no patients enrolled in 
Part 3 c, 
Part 4 is ongoing d 
NP27872 
Phase I, Dose-escalation, food-effect, 
and biomarker study 
Solid tumor, N = 99  
(Dose escalation, N = 48 
Biomarker cohorts, N = 37 
Food-effect, N = 10 
Apoptosis, N = 4) 
Idasanutlin 
monotherapy 
MBP 
Completed;  
NP28902 
Phase I, DDI with a strong CYP3A4 
inhibitor (Part 1), new formulations rBA 
(Part 2), and food-effect of optimized 
SDP formulation (Part 3) 
Solid tumor, N = 61 
(DDI Part 1, N = 20 f 
 
rBA Part 2, N = 12 f  
Part 3, N = 29 g  
Optional treatment extension, 
N = 20 f,h) 
Idasanutlin 
monotherapy 
Part 1 
Part 
2 = optimized 
MBP, initial 
SDP, SDP 
Part 3 = SDP 
Enrollment is 
complete. 
 
WO29519 
Phase III, multicenter, double-blind, 
randomized, placebo-controlled study of 
idasanutlin in combination with 
cytarabine compared with cytarabine 
plus placebo  
Relapsed/refractory AML, 
N = 440 
Idasanutlin in 
combination with 
cytarabine 
SDP 
Protocol in preparation 
 
 
 
 
 
 


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Protocol version date: 17Mar2020 
AML = acute myeloid leukemia; DDI = drug-drug interactions; IV = intravenous; MBP = micro-precipitated 
bulk powder; PK = pharmacokinetic; rBA = relative bioavailability; SDP = spray-dried bulk powder. 
a Data snapshot date, 26 February 2015. 
b Extension discontinued due to benefit (complete remission) not reaching sufficiently high levels to continue 
monotherapy development in this high-risk population. 
c Planned enrollment, approximately 15−20 patients. 
d Planned enrollment, approximately 12−18 patients. 
f As of the data snapshot date of 14 February 2014, a total of 9 patients were enrolled in the extension. 
g h 
Patients from the optional extension had previously participated in Part 1, 2 or 3. 
 
 
The first-in-human study, NP27872, is a multicenter, open-label, Phase I, dose-escalation 
study of single agent idasanutlin administered orally to patients with advanced malignancies 
except leukemia. 99 patients were enrolled in the study: a total of 37 patients have been 
enrolled into biomarker cohorts in order to gain preliminary information on prognostic, 
pharmacodynamic, and early response biomarkers and clinical efficacy at or below the MTD 
in preparation for Phase II clinical development (results not yet available). In addition, 
evaluation of the effect of food on the pharmacokinetic (PK) parameters of idasanutlin was 
conducted in a subgroup of 10 patients enrolled in Study NP27872.  
Study NP28902 is a multicenter, open label, crossover design, clinical pharmacology study to 
investigate idasanutlin with drug-drug interaction with posaconazole (Part 1, 20 patients) and 
relative bioavailability of new formulations of idasanutlin (Part 2, 12 patients), and food-
effect on the pharmacokinetics of a single dose with the optimized SDP formulation (Part 3, 
29 patients, not included in the data cut-off) in patients with solid tumors. A total of 61 
patients were enrolled and enrollment is closed. Twenty of the 61 patients continued into the 
optional treatment extension following completion of clinical pharmacology assessments. 
Nine of these twenty patients are included in the data cut-off. 
 
Study NP28679 is a multicenter, open-label Phase I/Ib study of idasanutlin in escalating 
doses as a single agent (Part 1); in combination with cytarabine (Part 2); or in combination 
with cytarabine and anthracycline (Part 3) in patients with AML, and to characterize the PK 
and safety profiles of the optimized SDP formulation at the recommended Phase II dose in 
combination with cytarabine (Part 4). The first patient received idasanutlin on 21 February 
2013. The study is ongoing and enrollment is expected to be completed in 2015.  
As of 25 February 2015, 105 patients have been enrolled in the study (29 in Part 1 [20 in dose 
escalation and 9 in extension] and 61 in Part 2 [23 in dose escalation and 38 in extension]. 
Dose escalation is now complete and enrollment closed in Part 1, Part 2 and their respective 
extension arms. Enrollment for Part 3 and 4 is ongoing and at time of clinical cut off, no 
patients were enrolled in Part 3 and 15 patients were enrolled in Part 4. 
 
Clinical Pharmacokinetics 
The half-life of idasanutlin was approximately 1 day. There was apparent dose-
proportionality for last-day (3, 5, or 15 depending on schedule) area under the curve (AUC) 
up to 2400 mg/day with ~ 50% inter-patient variability in patients with solid tumors 
(NP27872 data). No apparent difference in PK exposure was found between patients with 
solid tumors (Study NP27872) and patients with AML (Study NP28679) in the dose range of 
400 to 1600 mg daily × 5 days. Although there was a small sample size (N = 13), PK data 
from East Asian patients did not appear to differ from other patient ethnicities (mainly 
Caucasians). Age does not appear to have an impact on PK exposure. A drug-drug interaction 
study with posaconazole as a strong CYP3A4 inhibitor was conducted in 20 (18 evaluable) 


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Protocol version date: 17Mar2020 
patients with solid tumors. No change in maximum plasma concentration (Cmax) and 
modestly higher (32%) change in AUC were found with CYP3A4 inhibition with minimal 
increase (22% in Cmax and 23% in AUC) with simulated steady−state profiles. Since a 
strong CYP3A4 inhibitor was chosen for the study, all CYP3A4 inhibition risks are deemed 
negligible.  
 
Evaluable PK data are available for 12 patients in Part 2 (relative bioavailability) of Study 
NP28902 administered 400 mg reference MBP (micro-precipitated bulk powder), an 
improved 400 mg MBP, and a 400 mg SDP (spray-dried powder) formulations in randomized 
sequence on Days 1, 8, or 15 under fasting conditions. Overall, preliminary clinical PK 
results indicate that: idasanutlin exposure, based on AUC to the last measurable time point 
(AUC168h) and Cmax, was higher with the SDP formulation (42% and 47%, respectively) 
than the previous (reference) MBP formulation. The SDP will be the formulation in future 
trials including the current study. Part 3 of this study examined food-effect of a high 
energy/high-fat meal (1000 kcal with 50% from fat) and low-fat meal (500 kcal with 30% 
from fat) on PK. In 19 evaluable patients (receiving 3 crossover treatments) no evidence for a 
food-effect was demonstrated.Equivalence in all PK exposure parameters analyzed (90% 
confidence interval (CI)) was shown, while the low-fat meal demonstrated less than 20% 
increase in all PK exposure parameters, just outside the upper limit of 90% CI for 
bioequivalence. 
 
Clinical Pharmacodynamics 
Macrophage inhibitory cytokine ([MIC-1], a secreted protein that is strongly induced by 
activated p53) serum levels, has been used to assess pharmacodynamic effects in Study 
NP27872. Analysis of patients treated with 100 to 3200 mg/day of idasanutlin showed that 
the minimum level for p53 induction occurred at the lowest tested dose of 100 mg/day or a 
corresponding plasma level of 500 ng/mL of idasanutlin. There was no upper limit with the 
dose tested. However, a comparison of MIC-1 elevation between the idasanutlin dosing 
schedules demonstrated poor ability to activate p53 with the weekly schedule. 
 
Preliminary analysis of PK and safety data showed that there is an apparent pharmacokinetic / 
pharmacodynamic relationship between an AUC per cycle and Cycle 1 platelet nadir; this 
was mostly associated with the daily (× 5 days or × 3 days) dosing schedules; no correlation 
exists for the weekly schedule. No correlation was apparent between idasanutlin plasma 
concentration and QT corrected using Fridericia’s method (QTcF) for both solid tumor and 
AML patient populations, which suggests there was no apparent QT prolongation signal. 
 
Optimal Schedule 
Idasanutlin PK exposure, pharmacodynamic effects (e.g., MIC-1, as a p53 activation marker), 
and target-mediated hematological changes (platelet reduction in particular) were evaluated 
to support the optimal dosing schedule. A comparison of MIC-1 elevation between the 
idasanutlin dosing schedules demonstrated poor ability to activate p53 with the weekly 
schedule. The daily × 3 days dose regimen did not achieve steady-state exposure, achieved a 
shorter period of SD, and did not alleviate thrombocytopenia. Therefore, the daily × 5 days 
schedule is proposed as optimal for future clinical trials including the current study. 
 
Clinical Efficacy 
No relapsed solid tumor patients achieved a monotherapy response to idasanutlin, according 
to Response Evaluation Criteria in Solid Tumors (RECIST) in Study NP27872. Twenty-six 
(31%) patients had stable disease and remained on study an average of 64 days. Analysis in 
tumor tissues of PD biomarkers associated with the p53 pathway showed significant changes 


MC1582 
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Addendum 7 
 
Protocol version date: 17Mar2020 
upon dosing for most biomarkers in those patients having paired biopsies. These findings 
confirmed the proposed mechanism of action of idasanutlin activating the p53 pathway 
through MDM2 antagonism.  
 
Evaluable hematological malignancy response assessments from the NP28679 study were 
available for patients in Part 1, Part 1 EXT, Part 2, Part 2 EXT and Part 4 arms at time of 
clinical data cutoff date 25 February 2015. Response assessments were noted as follows:  
Part 1: Twenty (20) patients received monotherapy idasanutlin during Part 1 dose escalation 
at 400 mg (n = 2), 800 mg (n = 6) and 1600 mg (n = 12) daily x 5 days. Five (5) patients 
achieved marrow clearance on biopsy, Complete Remission/Complete Remission without 
platelet recovery (CR/CRp) [n=2] or Complete Remission with insufficient recovery of 
peripheral counts (CRi)/Morphologic Leukemia Free State (MLFS) [n=3]. 
Part 1 Extension: Nine (9) patients received monotherapy idasanutlin at 600 mg two times per 
day (BID) X 5 days. Best responses reported for the 8 evaluable patients were 2 CRi/MLFS, 
2 Hematologic Improvement (HI) and 4 Progression of Disease (PD). 
Part 2: Twenty-three (23) patients were enrolled in Part 2 dose escalation (idasanutlin and 
cytarabine) at daily doses of 400 mg (n = 10, with 1 ineligible patient), 800 mg (n =7), and 
1200 mg (n =6). Six (6) relapsed AML patients achieved CR/CRp. 
Part 2 Extension: Thirty-eight patients (38) with relapsed/refractory AML were enrolled to 
Part 2 extension randomized to idasanutlin 600 mg BID with (n=21) or without cytarabine 
(n=17). Thirty-three (33) patients have responses reported with 6 CR/CRps (5 in 
combination, 1 with idasanutlin monotherapy), 1 Partial Response (PR) [defined as >50% 
decrease in bone marrow blasts] (combination), 3 HI (monotherapy), 23 PD (13 with 
monotherapy and 10 with combination).  
Part 4: Fifteen patients (15) have enrolled in the Part 4 bridging arm with the SDP 
formulation in combination with cytarabine 1g/m2 x 6d as of 25 February 2015. Fourteen 
(14) patients have responses reported, with 4 CR/CRp, 1 PR, 2 HI, and 7 PD. 
 
Table 1-5 
Summary of Best Hematologic Malignancy Response over the Duration of 
Treatment-Study NP28679 
 
Part 1 
Dose 
Escalation 
Part 1 
Extension 
Part 2 
Dose 
Escalation 
Part 2 Extension 
Part 4 
 
idasanutlin (MBP) 
Monotherapy 
idasanutlin 
(MBP) plus 
Cytarabine 
idasanutlin 
(MBP) 
Monotherapy 
idasanutlin 
(MBP) plus 
Cytarabine 
idasanutlin 
(SDP) plus 
Cytarabine 
Enrolled 
20 
9 
23 
17 
21 
15 
Evaluable 
17 
8 
22 a 
17 
16 
14 
CR/CRp 
2 
0 
6 
1 
5 
4 
CRi/MLF
S 
3 
2 
1 
0 
0 
0 
PR 
3 
0 
2 
0 
1 
1 
HI 
4 
2 
2 
3 
0 
2 
PD 
5 
4 
10 
13 
10 
7 
Missing 
0 
0 
1 
0 
0 
0 


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Addendum 7 
 
Protocol version date: 17Mar2020 
CR = complete remission; CRi/MLFS = complete remission with incomplete recovery of 
peripheral counts/morphological leukemia-free state; CRp = complete remission with 
incomplete platelet recovery; HI = hematological improvement; PD = progressive disease; 
PR = partial response. 
a 1 patient did not have AML and was not evaluable. 
 
Clinical Safety 
In solid tumor studies of idasanutlin, consistent with the mechanism of action, p53 induction 
caused “on-target” toxicity in hematopoietic cells. Higher exposures led to adverse events of 
neutropenia and thrombocytopenia, which while reversible could reach grade 3/4 in some 
patients. Modeling of this toxicity demonstrated that cytopenias were exposure dependent, 
with delayed nadirs in blood counts. Recovery at higher exposures caused delays in 
subsequent cycles of therapy, which was alleviated by dose-reduction for subsequent cycles. 
• 
Most common AEs were diarrhea, nausea, vomiting, decreased appetite, and 
thrombocytopenia. 
• 
Most common severe AEs of NCI-CTC Grade 3 were thrombocytopenia, neutropenia, 
anemia, nausea, and diarrhea. 
• 
Most common SAEs were thrombocytopenia, febrile neutropenia, neutropenia, 
leukopenia, and anemia. 
• 
Seven (7) deaths occurred during the study, 5 due to progressive disease, and 2 due to 
fatal AEs (intra-abdominal hemorrhage, pulmonary embolism) 
 
Overall, the current safety profile of Study NP28679 in AML is consistent with findings from 
other studies of relapsed/refractory AML patients treated with cytarabine. For those patients 
receiving cytarabine with idasanutlin, there is a similarity of the safety profiles for the two 
agents. Specifically, they both may manifest AEs for gastrointestinal disorders, 
myelosuppression, febrile neutropenia, infection including pneumonia, or cellulitis. When 
both agents are given concurrently, it may not be possible to distinguish whether the IMP or 
the disease, if not both, may have contributed to the onset of a given AE. 
 
At the data cutoff date of 14 February 2014 for Study NP28902 and with final data for Study 
NP27872, 131 patients with advanced malignancies (excluding leukemia) had received 
idasanutlin. In the Phase I entry-into-human dose escalation study NP27872 there are 99 
patients with available data and the Phase I drug-drug interaction/relative bioavailability 
study NP28902 comprised 32 patients. All patients in both studies experienced at least one 
adverse event, and 32 of 99 patients in Study NP27872 and 5 of 32 patients in Study 
NP28902 experienced at least one serious adverse event. Of these 32 patients in Study 
NP27872, 25 experienced serious adverse events that were considered by the investigator to 
be possibly, probably, or remotely related to study treatment, almost all of which were related 
to hematopoietic or gastrointestinal toxicities. Of the 5 patients who reported an SAE in 
Study NP28902, only 1 patient experienced a serious adverse event of thrombocytopenia 
(Grade 4) considered by the investigator to be related to study treatment. A total of 18 
patients in Study NP27872 and 3 patients in Study NP28902 Part 1 
(idasanutlin+posaconazole) experienced adverse events that led to withdrawal from study 
treatment. 
 
The most frequently affected system organ classes (SOC; 10% of all patients) in Study 
NP27872 were gastrointestinal disorders (97/99 [98.0%]), general disorders and 
administration site conditions (74/99 [74.7%]), metabolism and nutrition disorders (63/99 
[63.6%]), blood and lymphatic disorders (50/99 [50.5%]), nervous system disorders (48/99 
[48.5%]), musculoskeletal and connective tissue disorders (45/99 [45.5%]), respiratory, 


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Addendum 7 
 
Protocol version date: 17Mar2020 
thoracic and mediastinal disorders (44/99 [44.4%]), infections and infestations (24/99 
[24.2%]), skin and subcutaneous tissue disorders (20/99 [20.2%]), investigations (19/99 
[19.2%]), psychiatric disorders and vascular disorders (13/99 [13.1%] each), and injury, 
poisoning, and procedural complications (10/99 [10.1%]) ([CD]). A summary of the most 
frequent AEs occurring in at least 10% of the patients in any treatment group is shown in 
Table 1-6. The five most frequent AEs of any grade were diarrhea (74/99 [74.7%]), nausea 
(71/99 [71.7%]), vomiting (51/99 [51.5%]), decreased appetite (47/99 [47.5%]), and 
thrombocytopenia (39/99 [39.4%]). 
 
Overall, two deaths in Study NP28902 and seven deaths in Study NP27872 were reported. In 
Study NP27872, five deaths were attributed to disease progression, and one death each to 
intra-abdominal hemorrhage and pulmonary embolism (unrelated) and pulmonary embolism 
(possibly related). In Study NP28902 the cause of death for 1 patient was attributed to disease 
progression and one patient died from unrelated aspiration pneumonia. 
 
Table 1-6. Summary of Adverse Events with an Incidence Rate of at Least 10% 
Study NP28902 
Total number of patients with at least one adverse 
event  
20 (100.0%) 
 Total number of events 
57 
 Diarrhea 
12 ( 60.0%) 
 Nausea 
10 ( 50.0%) 
 Vomiting 
4 ( 20.0%) 
 Abdominal pain 
1 ( 5.0%) 
 Fatigue 
4 ( 20.0%) 
 Dehydration 
3 ( 15.0%) 
 Abdominal distension 
1 ( 5.0%) 
 Decreased appetite 
2 ( 10.0%) 
 Hypomagnesaemia 
1 ( 5.0%) 
 Constipation 
2 ( 10.0%) 
 Dyspnea 
1 ( 5.0%) 
 Asthenia 
1 ( 5.0%) 
 Chest pain 
1 ( 5.0%) 
 Early satiety 
1 ( 5.0%) 
 
Consistent with other ongoing studies of RO5503781, gastrointestinal (GI) adverse events 
(AEs) including nausea, vomiting, and diarrhea were common (diarrhea reported by >90%), 
but manageable in the NP28679 study (per clinical cutoff date 25 February 2015) both as 
monotherapy and in combination with Cytarabine in AML patients. Other frequently reported 
AEs were infection related (78%). The maximum tolerated dose (MTD), as defined in 
Protocol NP28679, was not reached.  
 
Early deaths related to AML progression and infection was seen, as expected in the 
relapsed/refractory AML population.  
 
 


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Addendum 7 
 
Protocol version date: 17Mar2020 
 
1.7 Rationale for the current trial: In this trial we propose to evaluate the combination of 
ixazomib, an oral proteasome inhibitor, and idasanutlin, a p53 activator and dexamethasone 
in patients with 17p deleted MM. The approach is based on several hypotheses and available 
evidence. 
• 
Patients with TP53 deletion develop resistance very fast and remain the biggest 
stumbling block for successful control of this disease. Activating p53 will restore the 
sensitivity of the cell to current therapeutics and the combination is hence able to 
overcome drug resistance. This would be expected to be pronounced in cases where 
the remaining allele is of WT status, but not necessarily restricted to such. 
• 
Ixazomib has excellent activity in myeloma, relapsed and newly diagnosed, and 
offers the possibility of an all-oral regimen for 17p-deleted myeloma. In addition, 
Ixazomib has excellent soft tissue penetration and may be particularly helpful in 
patients with 17p-deleted myeloma, who often have extramedullary disease. Addition 
of dexamethasone enhances the activity of Ixazomib and hence will be added as part 
of the regimen. 
 


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Addendum 7 
 
Protocol version date: 17Mar2020 
2.0 
Objectives 
 
2.1 
Primary 
 
2.11 
Phase 1: The primary objective of the Phase 1 portion is to determine the 
maximum tolerated doses (MTD) of idasanutlin and ixazomib to be used in 
combination with dexamethasone in patients with relapsed or refractory multiple 
myeloma with TP53 (17p) deletion. 
 
2.12 
Phase 2: To evaluate the confirmed response rate of ixazomib and idasanutlin 
used in combination with dexamethasone in patients with relapsed or refractory 
multiple myeloma with TP53 (17p) deletion. 
 
2.2 
Secondary 
 
2.21 
Phase 1: To describe the toxicities and the confirmed response rate associated 
with the combination of idasanutlin, ixazomib and dexamethasone 
 
2.22 
Phase 2:  
 
2.221 To describe the toxicities associated with the combination of idasanutlin, 
ixazomib and dexamethasone 
2.222 To describe the CR and VGPR rates 
2.223 To assess progression-free and overall survival 
 
2.3 
Exploratory 
2.31 
Assess mdm2 inhibition in bone marrow plasma cells  
 
2.32 
Identify potential biomarkers associated with response. 
 
2.33 
To explore the pharmacodynamic effects of idasanutlin. 
 
 
 
 


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Addendum 7 
 
Protocol version date: 17Mar2020 
3.0 
Patient Eligibility 
 Enrollment open to Phase II as of Addendum 4 
 3.1 
Inclusion Criteria  
3.11 
Age ≥18 years. 
3.12 
Diagnosis of MM with deletion 17p (del17p) or monosomy 17 by FISH who 
have received at least one line of therapy. 
3.13 
The following laboratory values obtained ≤14 days prior to registration. 
• 
Calculated creatinine clearance (using Cockcroft-Gault equation below*) 
≥30 mL/min  
• 
AST (SGOT) and ALT (SGPT) ≤3.0 x upper limit of normal (ULN) 
• 
Total bilirubin ≤1.5 × the upper limit of the normal range (ULN) 
• 
Absolute neutrophil count (ANC) ≥1500/mm3  
• 
Platelet count ≥75,000/mm3 
• 
Hemoglobin ≥8.0 g/dL 
NOTE: White blood count and platelet count criteria must be met without any 
transfusion or growth factor support. 
*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 
Patients with measurable disease defined as at least one of the following: 
a. Serum monoclonal protein ≥1.0 g/dL by protein electrophoresis 
b. >200 mg of monoclonal protein in the urine on 24-hour electrophoresis  
c. Serum immunoglobulin free light chain ≥10 mg/dL AND abnormal serum 
immunoglobulin kappa to lambda free light chain ratio. 
 
3.15 
ECOG performance status (PS) 0, 1 or 2 (Appendix I). 
 
3.16 
Ability to understand the purpose and risks of the study and provide signed and 
dated informed consent and authorization to use protected health information. 
 
3.17 
Negative pregnancy test done ≤7 days prior to registration, for women of 
childbearing potential only. 
 
3.18 
Willing to follow strict birth control measures as suggested below. 
a) Female patients: If they are of childbearing potential (except if 
postmenopausal for at least 1 year before the screening visit, OR Are 
surgically sterile), 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, OR  
• 
Agree to practice true abstinence when this is in line with the preferred 
and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, 


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Addendum 7 
 
Protocol version date: 17Mar2020 
ovulation, symptothermal, post-ovulation methods] and withdrawal are 
not acceptable methods of contraception.) 
b) 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 
• 
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.) 
 
3.19a 
Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
 
3.19b Willing to provide bone marrow and blood samples for correlative research 
purposes (see Sections 6.2 and 14.1). 
 
3.2 
Exclusion Criteria 
3.21 
Other malignancy requiring active therapy. 
EXCEPTIONS: Non-melanoma skin cancer, DCIS or carcinoma-in-situ of the 
cervix.  
NOTE: If there is a history of prior malignancy, they must not be receiving other 
specific treatment for their cancer. 
 
3.22 
Other co-morbidity which would interfere with patient's ability to participate in 
trial, e.g. uncontrolled infection, uncompensated heart or lung disease. 
 
3.23 
Other concurrent chemotherapy, radiotherapy, 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. 
3.24 
Patient has >Grade 2 peripheral neuropathy, or Grade 1 with pain on clinical 
examination during the screening period. 
 
3.25 
Major surgery ≤14 days before study registration. 
 
3.26 
All CYP2C8 inhibitors, inducers, and substrates should be discontinued ≥7 days 
prior to registration. Systemic treatment with CYP2C8 inhibitors (anastrozole, 
montelukast, quercetin, trimethoprim, gemfibrozil, rosiglitazone, pioglitazone), 
inducers (carbamazepine, phenytoin, rifabutin, rifampin), or substrates 
(amiodarone, repaglinide, rosiglitazone, sorafenib, torsemide) should be 
discontinued ≥7 days prior to registration. 
 
3.27 
Systemic treatment with strong inhibitors of CYP3A4 (clarithromycin, 
telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, 
posaconazole) or strong CYP3A4 inducers (rifampin, rifapentine, rifabutin, 
carbamazepine, phenytoin, phenobarbital, Gingko biloba, St. John’s wort) are not 
allowed ≤14 days before registration. 


MC1582 
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Addendum 7 
 
Protocol version date: 17Mar2020 
 
3.28 
Evidence of current uncontrolled cardiovascular conditions, including cardiac 
arrhythmias, congestive heart failure, 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. 
 
3.29a 
QTc >470 milliseconds (msec) on a 12-lead ECG obtained during the Screening 
period. 
Note: If a machine reading is above this value, the ECG should be reviewed by a 
qualified reader and confirmed on a subsequent ECG. 
 
3.29b Known human immunodeficiency virus (HIV) positive. 
 
3.29c 
Known hepatitis B surface antigen-positive status, or known or suspected active 
hepatitis C infection. 
 
3.29d Any serious medical or psychiatric illness that could, in the investigator’s 
opinion, potentially interfere with the completion of treatment according to this 
protocol. 
 
3.29e 
Known allergy to any of the study medications, their analogues or excipients in 
the various formulations. 
 
3.29f 
Known GI disease or GI procedure that could interfere with the oral absorption 
or tolerance of ixazomib or idasanutlin including difficulty swallowing. 
 
3.29g Diarrhea >Grade 1, based on the NCI CTCAE grading, or currently taking 
antidiarrheals. 
 
3.29h Need for ongoing therapeutic anticoagulation. 
 
3.29i 
Female patients who are lactating or have a positive serum pregnancy test during 
the screening period. 
 
3.29j 
Patients that have previously been treated with ixazomib, or who participated in a 
blinded study with ixazomib (whether treated with ixazomib or not). 
 




MC1582 
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Addendum 7 
 
Protocol version date: 17Mar2020 
chemistry panel (sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose and uric acid) on Day 15 for Cycle 1 and 2 only. Thereafter, a full 
chemistry panel will be collected on or within 3 days prior to Day 1 of all subsequent cycles and at the end of treatment visit/safety follow-up visit. 
Results must be reviewed before dosing on Day 1 of any given cycle. 
5. Hematology (CBC including hemoglobin, hematocrit, WBC with complete differential, platelets) weekly for Cycle 1 and 2 only; for Cycles 3-6, 
hematology will be performed on Days 1 and 15. From Cycle 7 onwards, hematology will be performed on Day 1 only. Results must be available for 
review by the investigator before initiation of treatment. 
6. Pregnancy tests for females of childbearing potential. A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not undergone 
a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any 
time in the preceding 24 consecutive months). Initial pregnancy test is required ≤7 days prior to registration. 
7. EKG (ECG) and CXR: Results may be used if obtained ≤30 days prior to registration. 
8. Correlative Studies: bone marrow aspirate to be collected at study entry, end of Cycle 4, at suspected CR and PD; peripheral blood to be collected C1D1 
pre-dose; C1D1 6 hours post-dose; C1D6; C2D1 6 hours post-dose and at PD. 
9. Myeloma specific lab evaluations refers to: β2 Microglobulin, serum and 24-hour urine immunoelectrophoresis, serum immunoglobulin assay, 
Serum/urine immunofixation and serum free light chain with kappa/lambda ratio. (All are done at baseline; specific tests for subsequent cycles will be 
according to Section 11.2.) 
10. Bone marrow aspirate and biopsy - quantify % myeloma cell involvement; bone marrow sample for cytogenetics and fluorescent in situ hybridization 
(FISH). Repeat bone marrow biopsy/aspirate if CR or sCR is suspected and as appropriate to confirm achievement of response. Bone marrow aspirate 
and blood to be collected for correlative studies at study entry, end of Cycle 4, at suspected CR and PD. 
11. Extramedullary Disease: Assess by physical exam and/or radiologic evaluation at baseline and as clinically indicated. Disease that can be assessed by 
physical exam should be evaluated on Day 1 of each cycle. Disease that can be assessed by radiologic evaluation should be assessed according the 
IMWG criteria for evaluation of response. This may include computerized tomography (CT) scan, ultrasound, positron emission tomography [PET]/CT 
or MRI. The same method of assessment should be used at each evaluation for any individual patient. Assess the need to evaluate plasmacytomas to 
confirm response or progression every cycle. 
12. Skeletal survey: Results may be used if obtained within 30 days of enrollment. Survey includes: lateral radiograph of the skull, anteroposterior and 
lateral views of the spine, and anteroposterior views of the pelvis, ribs, femora, and humeri. 
13. Complete Patient Medication Diary for the study drugs (See Appendix II) 
14. AE assessment/toxicity evaluation includes a brief PE when clinically indicated. Patients experiencing drug related adverse events of grade ≥2 should be 
followed up monthly until the adverse event has resolved to less than or equal to Grade 1 or the event is believed to be chronic or the patient receives 
other anti-cancer therapy. If the subject will not be visiting the clinic, investigator may consider telephone contact with subject to establish stability and 
possible toxicities.  
15. 30 day Safety follow-up: An adverse events/toxicity evaluation should be completed approximately 30 days (±7 days) following the last cycle of 
treatment regardless for the reason of discontinuation, unless patient withdraws consent and refuses further evaluation. 
4.2 
Event Monitoring/Survival Follow-up 
 
Event Monitoring Phase1 
q. 3 months 
until PD 
At PD 
After PD  
q. 6 months 
Death 
New Primary 
Event Monitoring 
X 
X 
X 
X 
At each occurrence 
1. If a patient is still alive 3 years after registration, no further follow-up is required. 


MC1582 
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Addendum 7 
 
Protocol version date: 17Mar2020 
5.0 
Grouping Factor:  
5.1 
Phase: I vs. II 
 
6.0 
Registration Procedures 
6.1 
Registration 
6.11 
Phase I – Mayo and non-Mayo institutions – enrollment closed as of 
Addendum 4 
Prior to discussing protocol entry with the patient, call the MCCC Registration 
Office 
 to insure that a place on the protocol is open to the 
patient. 
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.  
 
6.12 
Phase II – Mayo and Non-Mayo institutions - enrollment open as of 
Addendum 4 
Non-Mayo Institutions: 
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. 
 
Mayo Institutions only: 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page 
and enter the remote registration/ randomization application. The 
registration/randomization application is available 24 hours a day, 7 days a week. 
Back up and/or system support contact information is available on the Web site. 
If unable to access the Web site, call the MCCC Registration Office at 
 between the hours of 8 a.m. and 5:00 p.m. Central Time (Monday through 
Friday). 
All Institutions: 
The instructions for the registration/randomization application are available on 
the MCCC web page (http://hsrwww.mayo.edu/ccs/training) and detail the 
process for completing and confirming patient registration. Prior to initiation of 
protocol treatment, this process must be completed in its entirety and a MCCC 
subject ID number must be available as noted in the instructions. It is the 
responsibility of the individual and institution registering the patient to confirm 
the process has been successfully completed prior to release of the study agent. 
Patient registration via the registration/randomization application can be 
confirmed in any of the following ways: 
• 
Contact the MCCC Registration Office
. If the patient 
was fully registered, the MCCC Registration Office staff can access the 
information from the centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 


MC1582 
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Addendum 7 
 
Protocol version date: 17Mar2020 
6.2 
Correlative Research 
A mandatory correlative research component is part of this study, the patient will be 
automatically registered onto this component (see Sections 3.19b and 14.0).  
6.3 
Verification 
Prior to accepting the registration, registration/randomization application will verify the 
following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
6.4 
IRB approval 
Documentation of IRB approval must be on file in the Registration Office before an 
investigator may register any patients.  
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office (fax: 
. 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 Registration Office is no longer necessary. 
 
6.5 
Treatment requirements 
Treatment on this protocol must commence at the recruiting institution under the 
supervision of a hematologist. 
 
6.6 
Treatment start 
Treatment cannot begin prior to registration and must begin ≤14 days after registration. 
 
6.7 
Pretreatment 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
 
6.8 
Baseline symptoms 
All required baseline symptoms (see Section 10.6) must be documented and graded. 
 
6.9a 
Study drug 
Study drug is available on site. 
 
6.9b 
Blood kits 
Blood kit is available on site for this patient. 
 


MC1582 
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Addendum 7 
 
Protocol version date: 17Mar2020 
7.0 
Protocol Treatment 
This is a sequential phase 1 followed by phase 2 design, which will allow us to assess the MTD of 
idasanutlin and ixazomib when used in combination, and estimate the efficacy of the 
combination.  
• 
Study drug dosing will span 3 weeks, with a 1-week "rest" in each 28-day cycle. 
• 
There will be no intra-subject dose escalation. Dose modifications for toxicity are 
outlined in Section 8.  
• 
All subjects are planned to receive treatment to disease progression, unacceptable toxicity 
or withdrawal of consent.  
• 
An individual subject will be considered off-treatment following a 30-day safety follow-
up period after the last cycle of treatment. 
 
7.1 
Treatment Schedule as of Addendum 4 
Table 7.1 
Drug 
Route 
Dose 
Schedule 
Each cycle is 28 days 
Ixazomib 
Oral 
Phase 1: As assigned at registration  
Phase 2: 4.0 mg 
(MTD from Phase I) 
 
Days 1, 8 and 15 
Idasanutlin 
Oral 
Phase 1: As assigned at registration 
Phase 2:  200 mg 
(MTD from Phase I) 
 
Days 1-5 
Dexamethasone 
Oral 
40 mg 
Days 1, 8, 15 and 22 
 
7.2 
Ixazomib  
• 
Subjects will receive ixazomib weekly for 3 weeks (Days 1, 8 and 15) with a week 
off of each 28 day cycle. 
• 
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 no sooner than 2 hours after a meal. 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.  
• 
Missed doses can be taken as soon as the patient remembers if the next scheduled 
dose is 72 hours or more away. A double dose should not be taken to make up for a 
missed dose. If the patient vomits after taking a dose, the patient should not repeat the 
dose but should resume dosing at the time of the next scheduled dose 
• 
No intra-subject dose escalation of ixazomib will be permitted at any time during 
study.  
• 
Procedures for ixazomib dose reductions and delays are summarized in Section 8.2,   
along with the criteria that must be met for retreatment with study drug. If a dose is 
missed due to toxicity, the dose will not be made up. 




MC1582 
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Addendum 7 
 
Protocol version date: 17Mar2020 
7.62 
Dose escalation or cohort expansion will only take place after 3 patients are fully 
assessed using the Common Terminology Criteria for Adverse Events (CTCAE) 
of the National Cancer Institute (NCI) version 4.03 following the completion of 
Cycle 1. 
7.63 
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. 
 
7.64 
Investigators are to contact the Study Chair as soon as any dose-limiting toxicity 
(DLT) occurs. 
 
7.65 
Definitions of DLT 
For this protocol, dose-limiting toxicity (DLT) will be defined as an adverse 
event attributed as unlikely, definitely, probably, or possibly related 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 
Febrile neutropenia defined as fever ≥38.5oC (38 >1 
hour) with grade ≥3 neutropenia 
Other Non-hematologic 
≥Grade 3 as per NCI Common Terminology Criteria 
for Adverse Events v 4.0** 
Dose Delay 
Any adverse event that causes a dose delay of >2 
weeks of the next intended dose  
Dose Reduction 
Any dose reduction for ixazomib and/or idasanutlin 
within Cycle 1 
*Adverse event attributed as unlikely, definitely, probably, or possibly related to the 
study medication. 
**Grade 3 nausea, vomiting, or diarrhea with maximal supportive treatment(s) will be 
considered dose limiting.  
 
 
 


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Addendum 7 
 
Protocol version date: 17Mar2020 
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 limit to 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. 
NOTE: If either of idasanutlin or ixazomib is discontinued, the patient can continue on the 
other drugs, unless specified otherwise in the dose modification tables. If both are 
discontinued, the patient will go to event monitoring (Section 4.2). 
ALERT: 
ADR reporting may be required for some adverse events (See Section 10) 
8.1 
Dose Levels for each drug in the combination 
(Based on Adverse Events in Tables 8.2-4) 
NOTE: For toxicities that are unrelated to dexamethasone (related to idasanutlin or 
ixazomib), idasanutlin should be dose reduced at the first instance of the adverse event 
followed by ixazomib. Thereafter the drugs reduced should alternate between idasanutlin 
and ixazomib.  
NOTE: Once Ixazomib is dose reduced to 2.3 mg, all subsequent dose reductions should 
be limited to idasanutlin. Patients cannot continue on idasanutlin alone, but can continue 
on ixazomib alone if idasanutlin is discontinued for toxicity.  
NOTE: Toxicities attributable to dexamethasone should lead to dose reduction only for 
dexamethasone. 
 
Table 8.1 - Dose Reduction Steps for Ixazomib 
STARTING 
Dose 
 
Dose reduction steps for ixazomib 
 
Step -1 
 
Step -2 
Step -3 
4 mg 
 
3 mg 
 
2.3 mg 
Discontinue  
 
Table 8.2 - Dose Reduction Steps for Idasanutlin 
STARTING 
Dose 
 
Dose reduction steps for idasanutlin 
 
Step -1 
Step -2 
Step -3 
200 mg 
 
100 mg 
50 mg 
Discontinue 
 
Table 8.3 - Dose Reduction Steps for Dexamethasone 
Starting Dose 
 
Dose reduction steps for dexamethasone 
 
Step -1 
Step -2 
 
Step -3 
Step -4 
40 mg 
 
30 mg 
20 mg 
 
12 mg 
8 mg 
Dexamethasone may be permanently discontinued after Cycle 12 or at the 
investigator’s discretion due to dexamethasone toxicity. 
 
If patients cannot tolerate lowest dose level of ixazomib AND idasanutlin they will go to 
event monitoring per Section 4.2. If dexamethasone is discontinued, the patient may 
continue treatment. 
NOTE: Any study drugs which are discontinued may not be restarted 


MC1582 
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Addendum 7 
 
Protocol version date: 17Mar2020 
 
8.11  
Instruction for initiation of a new cycle of therapy or restarting therapy after 
interruption during a cycle for toxicities 
A new cycle of treatment may begin on the scheduled Day 1 of a new cycle if: 
• 
The ANC is ≥1500/μL 
• 
The platelet count is ≥75,000/μL 
• 
Any other non-hematologic treatment -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, the subject will be 
evaluated weekly and a new cycle of therapy will be held until the toxicity has 
resolved as described above. 
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 monitoring. 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
8.2 
Dose modifications for ixazomib based on adverse events during a cycle 
NOTE: Refer to Section 8.1 for dose levels 
Table 8.2 
CTCAE 
System/Organ/
Class (SOC)* 
ADVERSE EVENT 
ACTION** 
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) 
Days 2-15: Ixazomib dose should be omitted on 
Day 8 and/or 15 as applicable 
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. The subsequent cycle will use the 
reduced dose.  
Skin and 
subcutaneous 
tissue disorders 
Rash, maculopapular,  
≥Grade 2 
 
Omit ixazomib till rash resolves to ≤Grade 1 (See 
Section 9.9a). Restart at same dose. If the rash 
recurs, reduce dose by one dose level. 
Any skin, Grade 4 
Discontinue ixazomib and remove patient from all 
study treatment 
Nervous 
System 
Disorders 
Newly developed Grade 1 
peripheral neuropathy with pain, 
≥Grade 2 peripheral neuropathy 
Reduce dose of ixazomib to the next lower dose 
level 


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Addendum 7 
 
Protocol version date: 17Mar2020 
Table 8.2 
CTCAE 
System/Organ/
Class (SOC)* 
ADVERSE EVENT 
ACTION** 
Nervous 
System 
Disorders 
Grade 2 neuropathy with pain or 
Grade 3 peripheral neuropathy 
Omit ixazomib until toxicity resolves or returns to 
baseline. When toxicity resolves, re-initiate 
ixazomib at the next lower dose level. 
 
Grade 4 peripheral neuropathy 
Omit ixazomib. 
Peripheral neuropathy should be monitored until 
toxicity resolves or returns to baseline. 
Upon recovery, if the patient has received clinical 
benefit from therapy with ixazomib, the 
investigator may consider restarting ixazomib at 
the next lower dose level. 
Other 
Any other non-hematological 
Grade 3 attributable toxicity 
except: 
Omit ixazomib depending on the attribution, until 
resolution to Grade ≤1 or baseline 
Restart at next lower dose. If a patient is already 
at the lowest drug level, go to event monitoring 
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 
 
Grade 4 Nonhematologic 
Toxicities 
Consider permanently discontinuing ixazomib – 
Exception if 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. 
 
 


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Addendum 7 
 
Protocol version date: 17Mar2020 
8.3 
Dose modifications for idasanutlin based on adverse events during a cycle 
NOTE: Refer to Section 8.1 for dose levels 
Table 8.3 
CTCAE 
System/Organ/Class 
(SOC)* 
ADVERSE EVENT 
ACTION** 
Blood and lymphatic 
system disorders 
Febrile neutropenia associated with 
fever (≥38.5º C) 
• Omit idasanutlin dose. 
• Follow CBC weekly. 
• Restart next cycle at one dose level lower 
for idasanutlin. 
• If febrile neutropenia is the only toxicity 
for which a dose reduction is required  
G-CSF may be used and the idasanutlin 
dose maintained 
Investigations 
Grade 3 neutrophil count decreased 
and sustained for 7 days  
or 
Grade 4 neutrophil count decreased 
 
Platelet count decreased 
≥Grade 3 (platelet count 
<50,000/mm³) 
• Omit idasanutlin dose. 
• Follow CBC weekly. 
• Restart next cycle at one dose level lower 
for idasanutlin. 
• If neutropenia is the only toxicity for 
which a dose reduction is required  
G-CSF may be used and the idasanutlin 
dose maintained 
Skin and subcutaneous 
tissue disorders 
Rash maculopapular  
Grade 2 or 3 
• Omit idasanutlin dose; follow weekly 
• Restart next cycle at one dose level lower 
for idasanutlin. 
Any rash  
Grade 4 
• Discontinue idasanutlin and remove 
patient from all study treatment 
Immune system 
disorders 
Allergic reaction  
Grade 2-3 
• Omit dose and follow at least weekly 
• Restart next cycle at one dose level lower 
for idasanutlin. 
Grade 4 
• Discontinue idasanutlin and remove 
patient from all study treatment 
Other non-hematologic 
adverse event  
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 
• Omit idasanutlin depending on the 
attribution, until resolution to Grade ≤1 
or baseline 
• Restart at next lower dose - If a patient is 
already at the lowest drug level, go to 
event monitoring 
Other non-hematologic 
adverse event 
Grade 4 Nonhematologic 
Toxicities 
• Consider permanently discontinuing 
idasanutlin – Exception if the investigator 
determines the patient is obtaining a 
clinical benefit 


MC1582 
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Addendum 7 
 
Protocol version date: 17Mar2020 
* 
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. 
 
8.4 
Dose modifications for dexamethasone based on adverse events during a cycle 
NOTE: Refer to Table 8.1 for dose levels 
Table 8.4 
CTCAE 
System/Organ/Class 
(SOC)* 
ADVERSE EVENT 
AGENT 
ACTION** 
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 and idasanutlin should be 
continued 
Gastrointestinal 
disorders 
Pancreatitis 
≥Grade 3 (Severe pain; 
vomiting; medical 
intervention indicated (e.g., 
analgesia, nutritional 
support)) 
Dexamethasone 
Discontinue dexamethasone and do 
not resume 
Ixazomib and idasanutlin 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 and idasanutlin should be 
continued 


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Addendum 7 
 
Protocol version date: 17Mar2020 
Table 8.4 
CTCAE 
System/Organ/Class 
(SOC)* 
ADVERSE EVENT 
AGENT 
ACTION** 
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 and idasanutlin should be 
continued 
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 and idasanutlin 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. 
 
 


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Addendum 7 
 
Protocol version date: 17Mar2020 
9.0 
Ancillary Treatment/Supportive Care 
9.1 
Oral hydration 
Patients are encouraged to drink at least 6 to 8 cups of liquid per day. 
9.2 
Disallowed concurrent treatment 
The following treatments 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 
9.3 
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. 
9.4 
Blood products and growth factors 
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. 
9.5 
Diarrhea 
Prophylactic antidiarrheals should be used in this protocol. All patients will receive 
loperamide 4 mg daily for the first 5 days. Diarrhea occurring despite the prophylaxis 
should be managed according to clinical practice, including the administration of 
antidiarrheals such as loperamide once infectious causes are excluded. Fluid intake 
should be maintained to avoid dehydration. Fluid deficit should be corrected before 
initiation of treatment and during treatment. Additional doses of loperamide at 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. 
Please monitor patients carefully for development of ileus. 
9.6  
Renal failure and Ixazomib 
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 principal investigator. All 


MC1582 
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Addendum 7 
 
Protocol version date: 17Mar2020 
necessary supportive care consistent with optimal patient care shall be available to 
patients as necessary. 
9.7 
Herpes Zoster prophylaxis 
Patients may be at an increased risk of infection including reactivation of herpes zoster 
and herpes simplex viruses. Prophylaxis with acyclovir 400 mg PO BID is recommended 
while on study therapy and for 1 month beyond the end of therapy. 
9.8 
Prohibited medications 
9.81 
Prohibitedenzyme inhibitors 
The following medications and procedures are prohibited during the study: 
Systemic treatment with any of the following metabolizing enzyme inhibitors is 
not permitted in this study. (Rationale: If there were to be a drug-drug interaction 
with an inhibitor, the idasanutlin exposure would be increased leading to a high 
probability of an adverse event.): 
• 
Strong inhibitors of CYP3A: clarithromycin, telithromycin, itraconazole, 
voriconazole, ketoconazole, nefazodone, and posaconazole 
• 
Strong inhibitors of CYP2C8: anastrozole, montelukast, quercetin, 
trimethoprim, gemfibrozil, rosiglitazone, pioglitazone 
9.82 
Prohibitedenzyme inducers 
Systemic treatment with any of the following metabolizing enzyme inducers 
should be avoided, unless there is no appropriate alternative medication for the 
patient’s use. (Rationale: Unlike with inhibitors if there were to be a drug-drug 
interaction with an inducer, idasanutlin or ixazomib exposure would be less - so 
there is a reduced chance of an adverse event. However, there may be less chance 
for an antitumor effect, but that is not an absolute reason to be taken off study):  
Strong CYP3A or CYP2C8 inducers: rifampin, rifapentine, rifabutin, 
carbamazepine, phenytoin, and phenobarbital. Extra caution should be exercised 
when using these medications concomitantly and incidence of any side effects 
should be carefully monitored.  
9.83 
Systemic treatment with CYP2C8 substrates (e.g. amiodarone, repaglinide, 
rosiglitazone, sorafenib, and torsemide). 
9.84 
Excluded foods and dietary supplements include St. John’s wort and ginkgo 
biloba. 
9.9a 
Erythematous Rash with or without Pruritus 
Rash with or without pruritus has been reported with ixazomib, primarily at the higher 
doses tested and when given with agents where rash is an overlapping toxicity. The rash 
may range from limited erythematous areas, macular and/or small papular bumps that 
may or may not be pruritic over a few areas of the body, to a more generalized eruption 
that is predominately on the trunk or extremities. Rash has been most commonly 
characterized as maculopapular or macular. To date, when it does occur, rash is most 
commonly reported within the first 3 cycles of therapy. The rash is often transient, self-
limiting, and is typically Grade 1 to 2 in severity.  
Symptomatic measures such as antihistamines or corticosteroids (oral or topical) have 
been successfully used to manage rash and have been used prophylactically in subsequent 
cycles. The use of a topical, IV, or oral steroid (e.g., prednisone ≤10 mg per day or 
equivalent) is permitted. Management of a Grade 3 rash may require intravenous 
antihistamines or corticosteroids. Administration of ixazomib (and/or other causative 


MC1582 
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Addendum 7 
 
Protocol version date: 17Mar2020 
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 (e.g., using a thick, alcohol-free 
emollient cream on dry areas of the body or oral or topical antihistamines). A rare risk is 
Stevens-Johnson Syndrome, a severe and potentially life-threatening rash with skin 
peeling and mouth sores, which should be managed symptomatically according to 
standard medical practice. Punch biopsies for histopathological analysis are encouraged 
at the discretion of the investigator. 
9.9b 
Thrombocytopenia 
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. Ixazomib and idasanutlin administration should be modified as noted as per 
dose modification recommendations in the protocol when thrombocytopenia occurs (see 
Section 8.2 and Section 8.3). 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. 
9.9c 
Neutropenia 
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. Growth factor support is not required but may be considered 
according to standard clinical practice. Idasanutlin and ixazomib administration should be 
modified as noted as per dose modification recommendations in the protocol when 
neutropenia occurs (see Section 8.2 and Section 8.3). Therapy can be reinitiated at a 
reduced level upon recovery of ANCs. 
9.9d 
Fluid Deficit 
Vitals should be assessed prior to start of each cycle as per Table 4.1. Dehydration should 
be avoided since ixazomib may cause vomiting, diarrhea, and dehydration. Patients 
should be encouraged to maintain adequate fluid intake. Acute renal failure has been 
reported in patients treated with ixazomib, commonly in the setting of the previously 
noted gastrointestinal toxicities and dehydration. Fluid deficit should be corrected before 
initiation of study drug and as needed during treatment to avoid dehydration. 
9.9e 
Hypotension 
Symptomatic hypotension and orthostatic hypotension with or without syncope have been 
reported with ixazomib. Blood pressure should be closely monitored while the patient is 
on study treatment and fluid deficit should be corrected as needed, especially in the 
setting of concomitant symptoms such as nausea, vomiting, diarrhea, or anorexia. 
Patients taking medications and/or diuretics to manage their blood pressure (for either 
hypo- or hypertension) should be managed according to standard clinical practice, 
including considerations for dose adjustments of their concomitant medications during 


MC1582 
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Addendum 7 
 
Protocol version date: 17Mar2020 
the course of the trial. Fluid deficit should be corrected before initiation of study drug and 
as needed during treatment to avoid dehydration. 
9.9f 
Posterior Reversible Encephalopathy Syndrome 
One case of posterior reversible encephalopathy syndrome, which ultimately resolved, 
has been reported with ixazomib. This condition is characterized by headache, seizures 
and visual loss, as well as abrupt increase in blood pressure. Diagnosis may be confirmed 
by magnetic resonance imaging (MRI). If the syndrome is diagnosed or suspected, 
symptom-directed treatment should be maintained until the condition is reversed by 
control of hypertension or other instigating factors. 
9.9g 
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 
excluded. 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
The site principal investigator is responsible for reporting any/all serious adverse events to the 
sponsor as described within the protocol, regardless of attribution to study agent or treatment 
procedure. 
The sponsor/sponsor-investigator is responsible for notifying FDA and all participating 
investigators in a written safety report of any of the following: 
• 
Any suspected adverse reaction that is both serious and unexpected. 
• 
Any findings from laboratory animal or in vitro testing that suggest a significant risk for 
human subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity. 
• 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not conducted by 
the sponsor, that suggest a significant risk in humans exposed to the drug 
• 
Any clinically important increase in the rate of a serious suspected adverse reaction over 
the rate stated in the protocol or Investigator’s Brochure (IB). 
Summary of SAE Reporting for this study  
(please read entire section for specific instructions): 
  
WHO: 
WHAT form: 
WHERE to send: 
All sites 
Pregnancy Reporting 
 
http://ctep.cancer.gov/protocolDevelopment/electronic
applications/docs/PregnancyReportFormUpdated.p
df 
Mayo Sites – attach to MCCC 
Electronic SAE Reporting Form 
  




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Addendum 7 
 
Protocol version date: 17Mar2020 
Events that would not typically be considered to meet the criteria for expedited reporting, but 
that for a specific protocol are being reported via expedited means in order to facilitate the 
review of safety data (may be requested by the FDA or the sponsor).  
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm) 
a. Identify the grade and severity of the event using the CTCAE version 4.0. 
b. Determine whether the event is expected or unexpected (see Section 10.2). 
c. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
d. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
e. Determine if other reporting is required (see Section 10.5). 
f. Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
NOTE: A severe AE is NOT the same as a serious AE, which is defined in Section 10.4. 
10.2 
Expected vs. Unexpected Events  
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, (if 
an investigator brochure is not required, otherwise described in the general 
investigational plan).  
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan. 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
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 or specificity, expedited reporting is required. 
NOTE: *The consent form may contain study specific information at the discretion of the 
Principal Investigator; it is possible that this information may NOT be included in the 
protocol or the investigator brochure. Refer to protocol or IB for reporting needs. 
10.3 
Attribution to agent(s) or procedure 
When assessing whether an adverse event (AE) is related to a medical agent(s) medical or 
procedure, the following attribution categories are utilized: 
Definite - The AE is clearly related to the agent(s)/procedure. 
Probable - The AE is likely related to the agent(s)/procedure. 
Possible - The AE may be related to the agent(s)/procedure. 


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Unlikely - The AE is doubtfully related to the agent(s)/procedure. 
Unrelated - The AE is clearly NOT related to the agent(s)/procedure. 
 
10.31 AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) 
on the SAME (Combination) 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. 
• An AE that occurs on a combination study must be assessed in accordance with the 
guidelines for investigational agents/interventions.  
• 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, unless hospitalization is required. Refer to Section 10.4 for 
specific AE reporting requirements or exceptions. 
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 or specificity, expedited reporting is 
required. 
• An increased incidence of an expected adverse event (AE) is based on the 
patients treated for this study at their site. A list of known/expected AEs is 
reported in the package insert or the literature, including AEs resulting from a 
drug overdose. 
• Commercial agent expedited reports must be submitted to the FDA via MedWatch 
3500A for Health Professionals (complete all three pages of the form). 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM0
48334.pdf 
  
10.4 
Required Reporting 
AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) on 
the SAME Arm 
NOTE: The combination of an investigational agent with a commercial agent is 
considered investigational. 
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. 
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. 
Expedited Reporting 


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An AE that occurs on a combination study must be assessed in accordance with the 
guidelines for CTEP 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. 
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. 
10.41 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 where the AE is listed in Section 15.0 of the protocol or the 
consent form* as EXPECTED. Any protocol specific reporting procedures 
MUST BE SPECIFIED BELOW and will supersede the standard Expedited 
Adverse Event Reporting Requirements  
(Note: These adverse events must still be reported through the routine reporting 
mechanism [i.e. Nadir/adverse events form]; see Footnote 1):  
Table 10.411 
System Organ Class (SOC) 
Adverse event/ 
Symptoms* 
CTCAE Grade at 
which the event will 
not be expeditedly 
reported1 
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 count 
≤Grade 4 
Blood and lymphatic system 
disorders 
Anemia 
≤Grade 4 
1 These exceptions only apply if the adverse event does not result in hospitalization or any other 
serious criteria outlined in Section 10.42. 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 
investigators ONLY if they exceed the expected grade of the event. 
*The consent form may contain study specific information at the discretion of the Principal 
Investigator; it is possible that this information may NOT be included in the protocol or the 
investigator brochure. 
 


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10.411 
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 abnormalities 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). 
10.412 Death 
• 
Any death occurring within 30 days of the last dose, regardless of 
attribution to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
• 
Any death occurring greater than 30 days with an attribution of 
possible, probable, or definite to an agent/intervention under an 
IND/IDE requires expedited reporting within 24-hours. 
Reportable categories of Death  
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal: A disorder characterized by cessation of life 
during the first 28 days of life. 
• 
Death NOS: A cessation of life that cannot be attributed to a 
CTCAE term associated with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or within one 
hour of the onset of symptoms) or an unobserved cessation of life 
that cannot be attributed to a CTCAE term associated with Grade 
5. 
• 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benign, malignant and unspecified (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 hours only if it is possibly, probably, or definitely related 
to the investigational agent/intervention. 
10.413 
Secondary Malignancy 
• 
A secondary malignancy is a cancer caused by treatment for a 
previous malignancy (e.g., treatment with investigational 
agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 






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10.44 Reporting of re-occurring SAEs 
ALL SERIOUS adverse events that meet the criteria outlined in table10.41 
MUST be immediately reported to the sponsor within the timeframes detailed in 
the corresponding table. This reporting includes, but is not limited to SAEs that 
re-occur again after resolution. 
 
 10.441 Special reporting requirements for Takeda 
AEs may be spontaneously reported by the patient and/or in response to an open 
question from study personnel or revealed by observation, physical examination, 
or other diagnostic procedures. Any clinically relevant deterioration in laboratory 
assessments or other clinical finding is considered an AE. When possible, signs 
and symptoms indicating a common underlying pathology should be noted as one 
comprehensive event. For serious AEs, the investigator must determine both the 
intensity of the event and the relationship of the event to study drug 
administration.  
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. 


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The SAE report must include at minimum: 
• 
Event term(s) 
• 
Serious criteria 
• 
Intensity of the event(s): Sponsor-investigator’s or sub-investigator’s 
determination. Intensity for each SAE, including any lab abnormalities, will 
be determined by using the NCI CTCAE version specified in the protocol, as 
a guideline, whenever possible. The criteria are available online at 
http://ctep.cancer.gov/reporting/ctc.html. 
• 
Causality of the event(s): Sponsor-investigator’s or sub-investigator’s 
determination of the relationship of the event(s) to study drug administration.  
Follow-up information on the SAE may be requested by Takeda. 
Intensity for each SAE, including any lab abnormalities, will be determined by 
using the NCI CTCAE version used at your institution, as a guideline, whenever 
possible. The criteria are available online at 
http://ctep.cancer.gov/reporting/ctc.html. 
In the event that this is a multisite study, the sponsor-investigator is responsible 
to ensure that the SAE reports are sent to Takeda Pharmacovigilance (or 
designee) from all sites participating in the study. Sub-investigators must report 
all SAEs to the sponsor-investigator so that the sponsor-investigator can meet 
his/her foregoing reporting obligations to the required regulatory agencies and to 
Takeda Pharmacovigilance, unless otherwise agreed between the sponsor-
investigator and sub-investigator(s). 
Relationship to all study drugs for each SAE will be determined by the 
investigator or sub-investigator by responding yes or no to the question: Is there a 
reasonable possibility that the AE is associated with the study drug(s)? 
Sponsor-investigator must also provide Takeda Pharmacovigilance with a copy 
of all communications with applicable regulatory authorities related to the study 
product(s), as soon as possible but no later than 4 calendar days of such 
communication. 
Suggested Reporting Form: 
• 
SAE Report Form (provided by Takeda) 
• 
US FDA MedWatch 3500A: 
http://www fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default htm 
• 
Any other form deemed appropriate by the sponsor-investigator 
Product Complaints 
A product complaint is a verbal, written, or electronic expression that implies 
dissatisfaction regarding the identity, strength, purity, quality, or stability of a 
drug product. Individuals who identify a potential product complaint situation 
should immediately contact MedComm Solutions and report the event. Whenever 
possible, the associated product should be maintained in accordance with the 
label instructions pending further guidance from a Takeda Quality representative. 
 
For Product Complaints 
• 
Phone: 
 
• 
E-mail
 
• 
FAX: 
 


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• 
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 
10.442 Special reporting requirements for idasanutlin 
Roche special requirements for idasanutlin are detailed in the Safety Data 
Exchange Agreement (SDEA). 
- 
The sponsor-investigator, Shaji Kumar, MD , shall be responsible 
for: tracking all protocol-defined AE and pregnancy reports,  
- 
evaluating AE and pregnancy reports, providing SAEs, pregnancy 
reports and AESIs to Roche within 1 business day of the awareness 
date on a Medwatch/CIOMS form electronically or by fax, 
- 
providing non serious AEs within the final study report upon the 
completion of the study. 
• 
The parties will ensure that all single case reports have been 
transmitted to Roche and received by Roche for reconciliation on a 
monthly basis. 
• 
Investigator shall be responsible for expedited reporting 
responsibilities for the study as sponsor (regulatory authorities, ethics 
committee, investigators). 
• 
Investigator, shall be responsible for the preparation of his own 
DSUR/IND annual report for the study. Roche agrees to forward to 
Investigator an executive summary of the Roche DSUR upon request 
for cross referencing. 
• 
Roche shall have the final say and control over safety crisis 
management issues relating to idasanutlin. 
• 
Roche shall be responsible for activities relating to the IB for 
idasanutlin. 
10.5 
Other Required Reporting 
10.51 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) in 
general, include any incident, experience, or outcome that meets all of the 
following criteria: 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
2. Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
Some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events. In other cases, 




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• 
Death Neonatal: A disorder characterized by cessation of life during the 
first 28 days of life.  
• 
Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
• 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benign, malignant and unspecified (including cysts and 
polyps) – Other (Progressive Disease)” under the system organ class 
(SOC) of the same name. Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) 
should be submitted. 
10.53 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 will 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 unless otherwise specified. 
10.55 Pregnancy, Fetal Death, and Death Neonatal  
If a female subject (or female partner of a male subject) taking investigational 
product becomes pregnant, the subject taking should notify the Investigator, and 
the pregnant female should be advised to call her healthcare provider 
immediately. The patient should have appropriate follow-up as deemed necessary 
by her physician. If the baby is born with a birth defect or anomaly, a second 
expedited report is required. 
Prior to obtaining private information about a pregnant woman and her infant, the 
investigator must obtain consent from the pregnant woman and the newborn 
infant’s parent or legal guardian before any data collection can occur. A consent 
form will need to be submitted to the IRB for these subjects if a pregnancy 
occurs. If informed consent is not obtained, no information may be collected. 


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In cases of fetal death, miscarriage or abortion, the mother is the patient. In cases 
where the child/fetus experiences a serious adverse event other than fetal death, 
the child/fetus is the patient. 
NOTE: When submitting Mayo Expedited Adverse Event Report reports for 
“Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, the potential risk of exposure 
of the fetus to the investigational agent(s) or chemotherapy agent(s) should be 
documented in the “Description of Event” section. Include any available medical 
documentation. Include this form: 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/Pregna
ncyReportFormUpdated.pdf 
10.551 
Pregnancy 
Pregnancy should be reported in an expedited manner as Grade 3 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC. Pregnancy should be followed until the outcome is 
known. 
10.552 
Fetal Death 
Fetal death is defined in CTCAE as “A disorder characterized by death 
in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation.” 
Any fetal death should be reported expeditiously, as Grade 4 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy loss)” under the Pregnancy, puerperium and perinatal 
conditions SOC. 
10.553 
Death Neonatal 
Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” that is felt by 
the investigator to be at least possibly due to the investigational 
agent/intervention, should be reported expeditiously.  
A neonatal death should be reported expeditiously as Grade 4 “General 
disorders and administration - Other (neonatal loss)” under the General 
disorders and administration SOC.  
10.6 
Required routine reporting 
10.61 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: 
CTCAE 
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 


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CTCAE 
SYSTEM/ORGAN/CLASS 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Vomiting 
X 
X 
# of Stools 
X 
 
Diarrhea 
 
X 
Constipation 
 
X 
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 
10.62 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 10.6: 
10.621 
Grade 2 AEs deemed possibly, probably, or definitely related to the 
study treatment or procedure. 
10.622 
Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
10.623 
Grade 5 AEs (Deaths) 
• 
Any death within 30 days of the patient’s last study treatment or 
procedure regardless of attribution to the study treatment or 
procedure. 
• 
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. 
10.63 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). 
 


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11.0 
Treatment Evaluation 
11.1  
Terms and definitions 
Serum or urine M spike of any level is not a requirement for entry into the study. If 
present, and meets criteria for measurable disease this will be followed for M protein 
response using IMWG uniform response criteria as described below. 
• 
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-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 
• Cases in which there are multiple peaks of same monoclonal 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-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 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. 
• 
Response terms: The following response terms will be used to define M protein 
response: 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 be 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 


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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-spike) 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-spike, serum 
free light chain, or urine M-spike. 
• 
Oligosecretory myeloma: Patient with multiple myeloma who has NEVER had 
“measurable” serum M-spike or urine M-spike, but has had a detectable monoclonal 
protein in his/her serum and/or urine and/or measurable serum free light chain.  
• 
Non-secretory myeloma: Patient with multiple myeloma who has NEVER had a 
detectable monoclonal 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 M protein Response (Must Be Done At Each Disease Measurement Visit 
except as indicated1,2) 
On Study Baseline Value 
SPEP 
24 hr 
UPEP2 
Ig FLC 
BM Bx 
Serum M-spike ≥1 g/dl, and urine M-spike≥200 mg/24 hrs 
X 
X 
 
 
Serum M-spike ≥1 g/dl, but urine M-spike <200 mg/24 hrs 
X 
 
 
 
Serum M-spike<1 g/dl, and urine M-spike≥200 mg/24 hrs 
 
X 
 
 
Serum M-spike <1 g/dl, urine M-spike <200 mg/24 hrs, but 
involved Ig FLC is ≥10 mg/dL 
 
 
X 
 
1  Immunofixation studies of both serum and urine 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  Bone marrow biopsy results do not need to be confirmed (i.e. repeated after 
documented response). 
11.3 
Confirmed response  
In order to be classified as an M protein 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 


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made by verification on two consecutive determinations. 
• 
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 or relapse 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. Although the definition for “relapse from CR (or sCR) 
is listed, this will be documented as a response category in ONLY those protocols 
evaluating disease free survival. 
Table 11.5 
CATEGORY 
RESPONSE CRITERIA a 
Stringent complete 
response (sCR)e 
• 
CR as defined below plus all of the following: 
• 
Normal serum FLC ratio  
• 
Absence of clonal cells in bone marrow by immunohistochemistry or 
immunofluorescence b 
• 
Not applicable for those patients who do not have a “measurable” serum 
M-spike, serum free light chain, or urine M-spike at baseline 
Complete response 
(CR) 
• 
Negative immunofixation of the serum and urine  
• 
<5% plasma cells in bone marrow  
• 
If at on study, the only measurable non-bone marrow parameter was FLC, 
normalization of FLC ratio 
Very good partial 
response (VGPR)e 
• 
PR as defined below plus all of the following: 
• 
Serum and urine M-component detectable by immunofixation but not on 
electrophoresis or 
• 
If at on study, serum measurable, ≥90% or greater reduction in serum M-
component plus urine M-component <100 mg per 24 h  
• 
If at on study, the only measurable non-bone marrow parameter was FLC, 
≥90% or greater reduction in the difference between involved and 
uninvolved free light chain levels 
• 
Not applicable for those patients who do not have a “measurable” serum 
M-spike, serum free light chain, or urine M-spike at baseline 


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Table 11.5 
CATEGORY 
RESPONSE CRITERIA a 
Partial Response 
(PR) 
• 
One of the following: 
 If at on study, serum and urine measurable, a ≥50% reduction of serum 
M-protein and reduction in 24-h urinary M-protein by ≥90% or to 
<200 mg per 24 h  
 If at on study, only serum measurable (but urine not), a ≥50% 
reduction of serum M-protein  
 If at on study, urine measurable (but serum not), a reduction in 24-h 
urinary M-protein by ≥90% or to <200 mg per 24 h  
 If at on study, the only measurable parameter was FLC, a ≥50% 
decrease in the difference between involved and uninvolved FLC 
levels  
Stable disease (SD) Not meeting criteria for sCR, CR, VGPR, PR, or progressive disease 
Progressive 
disease (PD) d 
Any one or more of the following:  
• 
Increase of 25% from lowest value in f 
 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 parameter was FLC, the difference 
between involved and uninvolved FLC levels (absolute increase must 
be >10 mg/dl) c  
 Bone marrow plasma cell percentage (absolute % must be ≥10%)c 
 Appearance of a new lesion(s), ≥50% increase from nadir in SPD of 
more than one lesion, or ≥50% increase in longest diameter of a 
previous lesion >1 cm in short axis. Lesions PET positive if PET 
positive prior to therapy  
Or any one or more of the following felt related to the underlying clonal plasma 
cell proliferative disorder 
 Hypercalcemia (≥11.5 mg/dl) if considered related to myeloma 
 Decrease in hemoglobin of ≥2 g/dl if considered related to myeloma 
 Serum creatinine level ≥2 mg/dl if considered related to myeloma 
a All response categories require two consecutive assessments made at anytime before the institution of any 
new therapy; complete and 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 Presence/absence of clonal cells is based upon the k/  ratio. An abnormal k/  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/  of >4:1 or <1:2.  
c Positive immunofixation alone in a patient previously classified as CR will not be considered progression. 
d 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. 
e Does not apply to EMD or PCL  
f 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. 
 
 
m
 
 
 
  
 
 
m
 
 
 
m
 
 
 
m
 
 
 
  
 
 
m
 
 
 
m
 
 
 
m
 
 
 
  
 
 
m
 
 
 
m
 


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12.0 
Descriptive Factors  
12.1 
Parameters followed for hematologic response (pick one): serum M-spike ≥1 g/dL and 
urine M-spike ≥200 mg/24 hours vs. serum M-spike ≥1g/dL only vs. urine M-spike 
≥200 mg/24 hours only vs. serum immunoglobulin free light chain ≥10 mg/dL. 
Distinguish between SPEP measurements versus quantitative IgA measurement for serum 
M-spike 
12.2      Phase I only:   Dose level (to be assigned by Registration Office):   
       -2 vs. -1 vs. 0 vs. 1 vs. 2 vs. 3 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient  
13.1 
Continuation 
Patients who are sCR, CR, VGPR, PR, or SD (or usCR, uCR, uVGPR, uPR) will 
continue treatment per protocol. 
13.2 
Progressive Disease 
Patients who develop progressive disease while receiving therapy will go to the event-
monitoring phase. 
13.3 
Off protocol for reasons other than PD 
Patients who go off protocol treatment for reasons other than PD will go to the event-
monitoring phase per Section 18.0. 
13.4 
Criteria for Discontinuation of Treatment 
Patients may discontinue treatment for the following reasons: 
• 
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 over 2 years) 
• 
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 when the patient 
discontinues treatment. Patients should go to event monitoring per Section 4.2, unless the 
patient refuses further study participation or is lost to follow-up. 
13.5 
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 guidance 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 


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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. 
13.6 
Ineligible 
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 at the discretion of the physician as long as there are 
no safety concerns, and the patient was properly registered.  
If the patient discontinues treatment, 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 4.2 of 
the protocol.  
• 
If the patient never received treatment, on-study material and the Off Treatment Form 
must be submitted. No further data submission is necessary. 
13.7 
Major violation 
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. The patient may continue treatment at the discretion of the physician as 
long as there are no safety concerns, and the patient was properly registered. If the 
physician decides treatment should be discontinued, the patient will go directly to the 
event monitoring phase per Section 4.2, and all data up until the point of confirmation of 
a major violation must be submitted. 
13.8 
Cancel 
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 Off Treatment Form must be 
submitted. No further data submission is necessary. 
 


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14.0 
Biospecimens 
14.1  
Summary Table of Research Blood and Body Fluid Specimens to be collected for this Protocol 
Table 14.1 Summary Table of Research Blood and Body Fluid Specimens to be collected for this Protocol 
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) 
Study 
Entry 
End of 
cycle 4 
At 
suspected 
CR 
At PD 
Process at 
site? (Yes 
or No) 
Temperature 
Conditions 
for Storage 
/Shipping 
Flow cytometry# 
Mandatory Peripheral 
blood 
EDTA 
(lavender) 
10 mL 
(1) 
See Table 14.2 for time 
points 
X 
No 
Cool Pak 
RNA Seq for p53 
driven genes# 
Mandatory Peripheral 
blood 
EDTA 
(lavender) 
10 mL 
(1) 
See Table 14.2 for time 
points 
X 
No 
Cool Pak 
MIC1 ELISA# 
See Table 14.2 for time 
points 
X 
No 
Cool Pak  
Genomic studies 
Mandatory 
Bone 
marrow 
aspirate 
ACD 
(yellow) 
6 ml 
(1) 
X 
X 
X 
X 
No 
Cool Pak 
Flow cytometry 
X 
X 
X 
X 
No 
Cool Pak 
# Additional samples on Cycle 1, Day 1 and 6, and Cycle 2, Day 1 
14.2 
Summary Table of Cycle 1 and 2 Research Blood 
 
Cycle 1 Day 1 
Cycle 1 Day 6 
Cycle 2 Day 1 
Predose 
(≤1 hour 
before dosing) 
1 hour post-
dose  
(+/-0.25 hr) 
3 hrs post 
(+/-0.5 hr) 
6 hrs post 
(+/-1 hr) 
(Post-day 5 dose 
24 hours  
+/-1 hour) 
Predose  
(≤1 hour 
before dosing) 
1hr post (+/-
0.25 hr) 
3 hr post 
(+/-0.5 hr) 
6 hrs post 
(+/-1 hr) 
Flow cytometry 
(peripheral blood) 
X 
 
 
X 
X 
 
 
 
X 
RNA Seq and MIC1 
ELISA 
(peripheral blood) 
X 
 
 
X 
X 
 
 
 
X 
 




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14.45 RNAseq analyses will be performed on baseline derived patient specimens from 
blood and/or bone marrow. In addition to unsupervised analyses for transcripts 
associated with response, a supervised analysis will be conducted for MDM2, 
XPC, BBC3(PUMA,) and p16 (ink4A.) Additionally, RNAseq analyses listed 
above may also be performed on post-dose specimens on days 5/6 to assess 
pharmacodynamic changes consistent with mechanism of action target 
engagement for enhanced p53 activity following administration of drug. 
 
 
 


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15.0 
Drug Information 
15.1 
Ixazomib 
15.11 Background: Ixazomib (MLN9708) is a second-generation small molecule 
inhibitor of the 20S proteasome that is under development for the treatment of 
non-hematologic malignancies, lymphoma, and multiple myeloma. 
Ixazomib (MLN2238) refers to the biologically active, boronic acid form of the drug 
substance, ixazomib citrate (MLN9708). The transition to MLN2238 occurs in any 
aqueous system. 
 
15.12 Formulation: The ixazomib (MLN9708) capsule drug product formulation 
consists of drug substance, microcrystalline cellulose, talc, and magnesium 
stearate. Seven different capsule strengths are manufactured: 0.2, 0.5, 2.0, 2.3, 
3.0, 4.0, and 5.5 mg; each capsule strength has a unique color. Dosage strength is 
stated as ixazomib (the active boronic acid). Ixazomib capsules are individually 
packaged in blisters. 
 
Matching placebo capsules have been manufactured for the 2.3, 3.0, 4.0, and 5.5 
mg ixazomib (MLN9708) capsules. The placebo capsules contain 
microcrystalline cellulose, talc, and magnesium stearate and are identical in color 
and size to the corresponding active dose. 
 
15.13 Preparation and storage: Ixazomib (MLN9708) capsules (0.2 mg, 0.5 mg, 2 
mg), individually packaged in blisters, can be stored at 2ºC to 8ºC or “Do not 
store above 25ºC. Do not freeze.” Ixazomib capsules (2.3 mg, 3 mg, 4 mg, and 
5.5 mg), individually packaged in blisters, can be stored at “2ºC - 8ºC” or “Do 
not store above 30ºC. Do not freeze.”   
 
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 (MLN9708) capsules must be administered as intact 
capsules and are not intended to be opened or manipulated in any way.  Capsules 


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Protocol version date: 17Mar2020 
should be taken on an empty stomach with approximately 8 oz (1 cup) of water at 
least 1 hour before or at least 2 hours after food 
. 
Ixazomib should not be taken if the patient has had a serious allergic reaction to 
boron or boron containing products. 
Capsules of ixazomib will also be referred to as study drug. Study drug will be 
supplied by Takeda/Millennium as capsules of 2.3-, 3.0- and 4.0 mg ixazomib. 
Patients should be instructed to swallow ixazomib capsules whole, with water, 
and not to break, chew, or open the capsules. Study drug should be taken on an 
empty stomach (no food or drink) at least 1 hour before or 2 hours after a meal. 
Each capsule should be swallowed separately with a sip of water. A total of 
approximately 8 ounces (240 mL) of water should be taken with the capsules. 
Missed doses can be taken as soon as the patient remembers if the next scheduled 
dose is 72 hours or more away. A double dose should not be taken to make up for 
a missed dose. If the patient vomits after taking a dose, the patient should not 
repeat the dose but should resume dosing at the time of the next scheduled dose. 
 
15.15 Pharmacokinetic (PK) 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. Ixazomib protein binding was 
subsequently investigated in plasma samples from 75 cancer patients including 
those with normal hepatic and renal function (N = 23), with severe renal 
impairment including patients with end-stage renal disease requiring 
hemodialysis (N = 18), or with moderate (N = 15) or severe (N = 19) hepatic 
impairment (Studies C16015 and C16018). These definitive studies demonstrated 
that ixazomib was 99% bound to plasma proteins and the extent of binding was 
not altered by severe renal impairment, moderate hepatic impairment, or severe 
hepatic impairment. 
 
c) Metabolism: Metabolism is expected to be the major mechanism of clearance 
(CL) of ixazomib as renal clearance contributes approximately 3.7% to CL/F and 
6.4% to CL At 0.1 and 0.5 μM substrate concentrations, which are closer to 
clinical concentrations of ixazomib following oral administration of 4 mg, non-
CYP mediated clearance was observed and seemed to play a major role in 
ixazomib clearance in vitro. At clinically relevant concentrations of ixazomib, no 
specific CYP isozyme predominantly contributes to ixazomib metabolism and 
non-CYP proteins may contribute to the clearance of ixazomib in different 
capacities. Therefore, at clinically relevant concentrations of ixazomib, minimal 
CYP-mediated DDIs with a selective CYP inhibitor would be expected. 
 


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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. A reduced 
starting dose of ixazomib is recommended for patients with severe renal 
impairment. Unbound systemic exposures of ixazomib are 27% higher in patients 
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, 
popular rash 
Uncommon (≥0.1% to <1%): generalized pruritis, generalized rash 
 


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Addendum 7 
 
Protocol version date: 17Mar2020 
Herpes zoster – antiviral prophylaxis should be considered in patients 
being treated with ixazomib to decrease the risk of herpes zoster 
reactivation. 
 
Rare but serious risks – intestinal obstruction, life-threatening severe 
skin rash (Steven Johnson syndrome, TEN, DRESS syndrome), thrombotic 
thrombocytopenic purpura, tumor lysis syndrome, renal failure, bowel 
blockage, 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: Investigational product will be supplied free of charge to 
trial participants by Takeda/Millennium Pharmaceuticals, Inc. 
Ixazomib Destruction: Investigational ixazomib (expired or end of study) should 
be destroyed on site according to the institution’s standard operating procedure. 
Be sure to document removal and destruction on drug accountability logs. 
 
 
 


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Addendum 7 
 
Protocol version date: 17Mar2020 
15.2 
Idasanutlin 
Please consult the most current Investigator’s Brochure for complete drug information. 
15.21 Background: Idasanutlin is a selective inhibitor of the tumor suppressor protein 
53 (p53) and murine double minute 2 (MDM2) binding that frees p53 from 
negative control and activates the p53 pathway in cancer cells, which leads to cell 
cycle arrest and apoptosis in vitro and in vivo. 
15.22 Formulation: Film-coated tablet at dosage strengths of 50 mg, 200 mg, 300 mg, 
and 400 mg. The tablets contain RO5503781-020 (spray-dried powder). All 
tablets contain the excipients copovidone, microcrystalline cellulose, 
croscarmellose sodium, crospovidone, colloidal silicon dioxide, magnesium 
stearate, and a film coat. The film coat of the 50 mg as well as 200 mg tablets 
consists of polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron 
oxide yellow, iron oxide red and iron oxide black. The film coat of the 300 mg 
dose strength consists of polyvinyl alcohol, titanium dioxide, polyethylene 
glycol, and talc. The film-coat of the 400 mg dose strength consists of polyvinyl 
alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide yellow.  
15.23 Preparation and storage: Film-coated tablets of idasanutlin should be stored 
under the recommended storage conditions: Do not store above 25°C. 
15.24 Administration: Refer to the treatment section for specific administration 
instructions. 
15.25 Pharmacokinetic information:  
Absorption: There was no major effect of high-fat or low-fat food on PK 
exposure. 
 
Protein binding: 99.99% 
 
Metabolism: The main human CYP enzymes responsible for RO5503781 
metabolism are CYP3A4/5 and CYP2C8.  CYP3A4 was found to be responsible 
for the formation of the oxidative metabolites (M1, M2, and M4) of RO5503781 
in human liver microsomes, and accounts for approximately 80% of the total 
metabolism in human liver microsomes. 
 
Half-life elimination: approximately 1 day 
 
Time to peak: 7.5 hours 
Excretion:  No parent idasanutlin was detected (<1%) in urine samples. 
Metabolite M4 (RO6802287) was the only major metabolite in human plasma 
samples.  No apparent difference in PK exposure was found between patients 
with solid tumors and patients with AML in the dose range of 400 to 1600 mg 
daily × 5 days.  PK data from East Asian patients did not appear to differ from 
other patient ethnicities (mainly Caucasians).  Race, Age (23-83), gender, body 
weight (42.2 − 132.1 kg), body surface area (1.322 −2.64 m2), concomitant 
cytarabine administration, disease status (AML vs solid tumor), and creatinine 
clearance (39.7 − 200.2 mL/min) does not appear to have an impact on PK 
exposure. 
 
 


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Addendum 7 
 
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15.26 Potential Drug Interactions:  
Idasanutlin has a low potential for drug-drug interaction as a perpetrator with 
CYP1A2, 2C9, 2C19, 2D6, or 3A4, P-gp, BCRP, and CYP2B6 but a higher 
potential for DDIs with CYP2C8 substrates.  Idasanutlin is metabolized by 
multiple metabolic enzymes, mainly byglucuronidation (65%−80%) and to a 
lesser extent by oxidation via CYP2C8 and CYP3A4/5. Strong inhibitors and/or 
inducers of these enzymes may affect idasanutlin exposure. However, a human 
study with a strong CYP3A4 inhibitor suggested a minimal effect of idasanutlin 
exposure. CYP2C8 inhibitors are to be avoided when CYP3A4 inhibitors are 
allowed. Gemfibrozil, an UGT inhibitor, is also a CYP2C8 inhibitor that is 
excluded. The M4 metabolite of idasanutlin is an OATP B1/3 transporter 
inhibitor and thus concomitant use of statins should be avoided. 
 
15.27 Known potential toxicities: 
 
Very common (≥10%): diarrhea, nausea, vomiting, decreased appetite, 
thrombocytopenia, neutropenia, febrile neutropenia, sepsis, anemia, pneumonia, 
pyrexia, fatigue, asthenia, fungal infections, electrolyte disorders (hypokalemia, 
hypomagnesemia, hypophosphatemia, hypercalcemia, hypernatremia, 
hypocalcemia, hyponatremia, and hyperphosphatemia) 
 
Common (1%- <10%): tumor lysis syndrome 
 
Uncommon (0.1%- <1%): leukopenia  
 
Serious potential risks: supraventricular arrhythmias, hepatic toxicity, 
pulmonary embolism  
 
Special populations:  
Idasanutlin should not be administered to pregnant women. It is not known 
whether idasanutlin is excreted in human milk.  It has not been studied in 
pediatric, therefore idasanutlin should not be administered to this patient 
population 
Treatment with idasanutlin in patients with specific medical conditions 
such as mild heart failure, pulmonary insufficiency, or inadequately 
controlled diabetes mellitus has not been formally evaluated.  It is 
recommended to avoid treatment in diabetic patients not optimally 
controlled with medical management (e.g., presence of ketoacidosis). 
 
 


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15.28 Drug procurement: 
Idasanutlin will be supplied free of charge to trial participants by F. Hoffmann-
La Roche LTD. 
The Site Investigator will maintain records of each shipment of investigational 
product. The records will document shipment dates, method of shipment, batch 
numbers, product presentation and quantity of bottles contained in the shipment. 
Upon receipt of the investigational product, the designated recipient at the study 
site will inspect the shipment, verify the number and condition of the bottles, and 
prepare an inventory or drug accountability record. 
Investigational idasanutlin (expired or end of study) should be destroyed on site 
according to the institution’s standard operating procedure. Drug destruction 
records must be readily available for inspection by representatives of the MMRC 
and by regulatory authorities. 
 
15.29  Nursing Guidelines: 
15.291 Gastrointestinal side effects including diarrhea, nausea, and vomiting 
were commonly seen. Treat symptomatically and monitor for 
effectiveness. 
 
15.292 Cytopenias have also been seen. Monitor CBC w/diff and instruct 
patients to report any unusual bruising or bleeding to study team. Also 
instruct patients on sign symptoms of infection.  
 
15.293 Pneumonia has been seen. Instruct patients to report any SOB, cough or 
chest pain to study team immediately. 
 
15.294 Due to early investigation nature of agent, not all side effects can be 
known at this time. Instruct patients to report any symptoms or side 
effects to the study team. 
 
15.295 Pyrexia has been reported. Treat symptomatically and monitor for 
effectiveness. 
 
15.296  Electrolyte abnormalities are common, which may be an early sign of 
TLS. Monitor CMP and report any abnormalities to the study physician. 
 
15.297  Patients may experience fatigue, instruct in energy conserving lifestyle 
and monitor for effectiveness. 
 
15.298  Rarely Tumor lysis  syndrome has been seen. Monitor electrolytes, 
especially in patients with high tumor burden. 
 
15.3 
Dexamethasone for Oral Administration (DXM) 
15.31 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. 
15.32 Formulation: Commercially available for oral administration as:  


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Addendum 7 
 
Protocol version date: 17Mar2020 
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) 
15.33 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. 
15.34 Administration: Refer to the treatment section for specific administration 
instructions. May be taken with meals to decrease GI upset.  
15.35 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 
15.36 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. 
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) 
 
15.37 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 


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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. 
 
15.38 Drug procurement: Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
16.0 
Statistical Considerations and Methodology  
16.1 
Overview 
This is a Phase I/II study of a novel regimen of idasanutlin and ixazomib in combination 
with dexamethasone in patients with 17p deleted relapsed multiple myeloma. The Phase I 
study is designed to determine the maximally tolerated dose (MTD) and toxicity profile 
of ixazomib and idasanutlin in combination with dexamethasone in patients with relapsed 
multiple myeloma using the standard cohort 3+3 design. The Phase II portion is designed 
to assess the confirmed response rate associated with therapy with ixazomib and 
idasanutlin in combination with dexamethasone, in patients with 17p deleted relapsed 
multiple myeloma. 
16.11 Primary Endpoint 
The primary endpoint of the phase I portion of this trial is to assess the maximum 
tolerated dose (MTD) of ixazomib and idasanutlin in combination with 
dexamethasone. 
The primary endpoint of the phase 2 portion is the rate of confirmed response. A 
confirmed response is defined as a patient who has achieved an sCR, CR, VGPR, 
or PR on two consecutive evaluations. All patients meeting the eligibility criteria, 
who have signed a consent form and have begun treatment will be evaluable for 
response, unless they are determined to be a major violation. 
16.12 Sample Size 
The phase I portion of this study is expected to require a minimum of 9 and a 
maximum of 24 evaluable patients, but will likely have 15 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 26 additional evaluable patients will be accrued 
at the MTD dose level for a maximum of 32 evaluable patients in the phase II 
portion of this study. We anticipate accruing up to 3 additional patients in the 
phase II portion to account for ineligibility, cancellation, major treatment 
violation, or other reasons. Therefore, a maximum of 24 patients will be accrued 
in the phase I portion and a maximum of 29 patients will be accrued to the phase 
II portion for an overall maximum of 53 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 8 and 20 months. The phase II portion of this study will 
accrue in the subsequent 8-10 months. The maximum total study duration is 
expected to be approximately 3 years, or until the last patient accrued has been 
observed for at least 6 months. 


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16.2 
Phase 1 Study Design 
The primary endpoint of the phase I portion of this trial is to estimate the MTD of 
idasanutlin and ixazomib in combination with dexamethasone. A standard 3+3 phase I 
design will be utilized. 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 7.65 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 7.6.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 in 
at least 2 of 6 patients, then the MTD will have been exceeded and 
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 


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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 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  Confirmed response Profile  
A confirmed response is defined to be an sCR, CR, VGPR, or PR noted 
as the objective status on two consecutive evaluations. Confirmed 
response will be evaluated using all cycles of treatment. All patients 
meeting the eligibility criteria who have signed a consent form and have 


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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.  
 
16.3  Phase II Statistical Design 
 
16.31 Decision Rule 
In previous single agent studies in patients with relapsed or refractory myeloma, 
response rates of 19-30% have been seen.(Leleu, Karlin et al. 2015) A response 
rate higher than 25% for idasanutlin and ixazomib in combination with 
dexamethasone would be of interest in patients with relapsed 17p deleted 
multiple myeloma.  
The largest success proportion where the proposed treatment regimen would be 
considered ineffective in this population is 25%, and the smallest success 
proportion that would warrant subsequent studies with the proposed regimen in 
this patient population is 45%. The following one-stage binomial design uses 32 
evaluable patients to test the null hypothesis that the true success proportion in a 
given patient population is at most 25%.  
16.311 Final Decision Rule: If 11 or fewer successes are observed in the first 32 
evaluable patients, we will consider this regimen ineffective in this 
patient population. Otherwise, if the number of successes is at least 12, 
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 final decision 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 .08, i.e. there is a 8% 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... 
0.25 
0.30 
0.35 
0.40 
0.45 
Then the probability of declaring 
that the regimen warrants further 
study is… 
0.08 
0.23 
0.45 
0.68 
0.85 
 
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 
16.4 
Analysis Plan 
The analysis for this trial will commence at planned time points (see 16.3) and at the time 
the patients have become evaluable for the primary endpoint. The Statistician and Study 
Chair will make the decision, in accord with CCS Standard Operating Procedures, 


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availability of data for secondary endpoints (e.g., laboratory correlates), and the level of 
data maturity. It is anticipated that the earliest date in which the results will be made 
available via manuscript, abstract, or presentation format is when last patient has been 
followed for at least 6 months. 
 
16.41 Primary Outcome Analyses: 
16.411 Definition: The primary endpoint of this trial is the proportion of patients 
who achieve a confirmed response. A confirmed response is defined as 
an sCR, CR, VGPR, or PR noted as the objective status on two 
consecutive evaluations. All patients meeting the eligibility criteria who 
have signed a consent form and have begun treatment will be evaluable 
for response, unless they are determined to be a major violation. 
16.412 Estimation: 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 proportion will be 
calculated. 
 
16.42 Secondary Outcome Analyses 
16.421 The rate of CR will be estimated by the number of patients with an sCR 
or CR or divided by the total number of evaluable patients. The rate of 
PR will be estimated by the number of patients with a VGPR or PR 
divided by the total number of evaluable patients. Exact binomial 95% 
confidence intervals for the true success proportions will be calculated. 
16.422 Overall survival is defined as the time from registration to death due to 
any cause. The distribution of overall survival will be estimated using 
the method of Kaplan-Meier (Kaplan and Meier, 1958).  
16.423 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 
16.424 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. 
16.43 Correlative Analyses: Due to the small overall sample size, the results of these 
analyses will be considered exploratory and hypothesis-generating in nature. 
16.431 Effect of inhibition of mdm2 will be assessed by measuring MIC levels. 
MIC levels at each time point and changes after treatment will be both 
graphically and quanitatively summarized and explored. Changes from 
baseline will be evaluted using Wilcoxon’s signed rank test. 
16.432  Impact of mdm2 inhibition on activation of p53 and clonal selection will 
be examined using gene expression profiling and exome sequencing. 
16.433 Potential biomarkers associated with response will be assessed in an 
exploratory manner.Potential markers will be determined using gene 


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expression profiling.The correlation between potential biomarkers and 
response (responders vs. non-responders) will be evaluated using 
Fisher’s exact and Wilcoxon rank sum tests, 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 final decision 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 principal 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 
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: 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. 
16.521 
Phase I (includes all phase I patients):  
By the nature of the “cohorts of three” phase I study design, stopping 
rules are in place for each dose level. Specifically, if 2 or more dose-
limiting toxicities (DLTs) are observed during cycle 1 at any given 
dose level, accrual to that dose level will be stopped, and patients will 
be accrued to the next lower dose level until a maximum of 6 patients 
are treated at the lower level. Note that a DLT that affects dose 
escalation is only that which is observed in the first cycle of treatment. 
However, all cycles will be reviewed and the study team will 
determine whether the dose level needs to be adjusted for future 
patients if ≥2 in the first 3 patients OR ≥3 in the first 6 patients 
experience a Grade 4 or higher non-hematologic adverse event with an 
attribution of unlikely, possibly, probably, or definitely related to 
treatment over all cycles at any given dose level. 
 
16.522 
Phase II (includes all phase II patients, including phase I patients 
treated at the MTD): 
Accrual will be temporarily suspended to this study if at any time we 
observe events with an attribution of unlikely, possibly, probably, or 
definitely related to study treatment that satisfy one of the following: 
• 
if 7 or more patients in the first 15 treated patients experience a 
grade 4 or higher non-hematologic adverse event  
• 
if after the first 15 patients have been treated, 40% of all patients 
experience a grade 4 or higher non-hematologic adverse event.  


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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 3 years after the study opens to accrual. 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 6 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 
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: 
 
 


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Protocol version date: 17Mar2020 
16.731 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 
18 
34 
0 
52 
Ethnic Category: Total of all subjects* 
18 
35 
0 
53 
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 
17 
34 
0 
51 
Racial Category: Total of all subjects* 
18 
35 
0 
53 
 
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 
Data submission instructions for this study can be found in the Case Report Form 
packet. 
18.2 
Event monitoring 
See Section 4.2 and data submission table in the case report form packet for the 
event monitoring schedule. 
18.3 
CRF completion for non-Mayo Clinic sites 
This study will use Medidata Rave® for remote data capture (rdc) of all study data. 
18.4 
Site responsibilities 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.5 
Supporting documentation 
This study requires supporting documentation for diagnosis and progression prior to 
study entry as well as for evidence of response to study therapy and progression after 
study therapy. Supporting documentation for diagnosis will include either a pathology 
report or a laboratory report demonstrating multiple myeloma with extramedullary 
disease or plasma cell leukemia (including bone marrow biopsy report; and SPEP, UPEP, 
FLC, FISH, and Cytogenetics reports). These reports should be submitted within 14 days 
of registration. 
For progression of disease prior to study entry, supporting documentation includes the 
evidence needed to determine the patient’s progression prior to enrollment. These 
documents should be submitted within 14 days of registration. 
For response to treatment, supporting documentation includes SPEP, UPEP, FLC, Serum 
and Urine Immunofixation, Bone Marrow Biopsy and aspirate, and X-ray skeletal survey. 
For patients who progress after study therapy supporting documentation may include any 
of the following: SPEP, UPEP, FLC, serum and urine immunofixation, bone marrow 
biopsy and aspirate, and X-ray skeletal survey. 
18.6 
Labelling of materials 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.7 
Incomplete materials 
Any data entered into a form will result in that form being marked as “received.” 
However, missing data will be flagged by edit checks in the database. 
 
 


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18.8 
Overdue lists 
A list of overdue materials is automatically available to each site at any time. A list of 
overdue materials and forms for study patients will be generated monthly. The listings 
will be sorted by location and will include the patient study registration number. The 
appropriate co-sponsor/participant will be responsible to submit the overdue material. 
18.9 
Corrections forms 
If a correction is necessary the QAS will query the site. The query will be sent to the 
appropriate site to make the correction in the database and respond back to the QAS.  
 
19.0 
Budget 
 
19.1 
Costs charged to patient: Routine clinical care 
 
19.2 
Tests to be research funded: None 
 
19.3 
Other budget concerns: None 
 
 
 


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20.0 
References 
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myeloma: an overview of 6,633 patients from 27 randomized trials. Myeloma Trialists' Collaborative 
Group." J Clin Oncol 16(12): 3832-3842. 
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Yakoub-Agha, L. Garderet, G. Marit, L. Michaux, L. Voillat, M. Renaud, B. Grosbois, G. Guillerm, L. 
Benboubker, M. Monconduit, C. Thieblemont, P. Casassus, D. Caillot, A.-M. Stoppa, J.-J. Sotto, M. 
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L. Harousseau, T. Facon and C. Mathiot (2007). "Genetic abnormalities and survival in multiple 
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Benboubker, M. Monconduit, C. Thieblemont, P. Casassus, D. Caillot, A. M. Stoppa, J. J. Sotto, M. 
Wetterwald, C. Dumontet, J. G. Fuzibet, I. Azais, V. Dorvaux, M. Zandecki, R. Bataille, S. Minvielle, J. 
L. Harousseau, T. Facon and C. Mathiot (2007). "Genetic abnormalities and survival in multiple 
myeloma: the experience of the Intergroupe Francophone du Myelome." Blood 109(8): 3489-3495. 
Avet-Loiseau, H., J. Y. Li, C. Godon, N. Morineau, A. Daviet, J. L. Harousseau, T. Facon and R. Bataille 
(1999). "P53 deletion is not a frequent event in multiple myeloma." Br J Haematol 106(3): 717-719. 
Bergsagel, P. L. and W. M. Kuehl (2005). "Molecular pathogenesis and a consequent classification of 
multiple myeloma." J Clin Oncol 23(26): 6333-6338. 
Chang, H., C. Qi, Q. L. Yi, D. Reece and A. K. Stewart (2005). "p53 gene deletion detected by 
fluorescence in situ hybridization is an adverse prognostic factor for patients with multiple myeloma 
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Chng, W.-J., S. Van Wier, G. Ahmann, T. Price-Troska, K. Henderson, M. Chesi, T.-H. Chung, S. Kim, J. 
Carpten, M. Gertz, S. V. Rajkumar, M. Lacy, R. Kyle, P. Greipp, A. Dispenzieri, P. L. Bergsagel and R. 
Fonseca (2005). "Gene Expression Profiling of Hyperdiploid Multiple Reveal Complex Gene Dosage 
Effects and an mRNA Translation/Protein Synthesis Signature." Blood 106(11): 1538-. 
Chng, W. J., T. Price-Troska, N. Gonzalez-Paz, S. Van Wier, S. Jacobus, E. Blood, K. Henderson, M. 
Oken, B. Van Ness, P. Greipp, S. V. Rajkumar and R. Fonseca (2007). "Clinical significance of TP53 
mutation in myeloma." Leukemia 21(3): 582-584. 
Drach, J., J. Ackermann, E. Fritz, E. Kromer, R. Schuster, H. Gisslinger, M. DeSantis, N. Zojer, M. Fiegl, 
S. Roka, J. Schuster, R. Heinz, H. Ludwig and H. Huber (1998). "Presence of a p53 gene deletion in 
patients with multiple myeloma predicts for short survival after conventional-dose chemotherapy." Blood 
92(3): 802-809. 
Fonseca, R., P. L. Bergsagel, J. Drach, J. Shaughnessy, N. Gutierrez, A. K. Stewart, G. Morgan, B. Van 
Ness, M. Chesi, S. Minvielle, A. Neri, B. Barlogie, W. M. Kuehl, P. Liebisch, F. Davies, S. Chen-Kiang, 
B. G. Durie, R. Carrasco, O. Sezer, T. Reiman, L. Pilarski and H. Avet-Loiseau (2009). "International 
Myeloma Working Group molecular classification of multiple myeloma: spotlight review." Leukemia 
23(12): 2210-2221. 
Gertz, M. A., M. Q. Lacy, A. Dispenzieri, P. R. Greipp, M. R. Litzow, K. J. Henderson, S. A. Van Wier, 
G. J. Ahmann and R. Fonseca (2005). "Clinical implications of t(11;14)(q13;q32), t(4;14)(p16.3;q32), and 
-17p13 in myeloma patients treated with high-dose therapy." Blood 106(8): 2837-2840. 


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Gupta, N., M. Saleh and K. Venkatakrishnan (2011). "Flat-dosing versus BSA-based dosing for 
MLN9708, an investigational proteasome inhibitor: population pharmacokinetic (PK) analysis of pooled 
data from 4 phase-1 studies. ." Blood 118(21): 1433. 
Gupta, N., M. Saleh and K. Venkatakrishnan (2012). "Switch from BSA-based dosing to fixed dosing for 
the investigational drug ixazomib citrate: Application of modeling and simulation to influence posology 
decisions in oncology drug development. ." Clin Pharmacol Ther 91(S86-S87 ). 
Kumar, S., R. Fonseca, R. P. Ketterling, A. Dispenzieri, M. Q. Lacy, M. A. Gertz, S. R. Hayman, F. K. 
Buadi, D. Dingli, R. A. Knudson, A. Greenberg, S. J. Russell, S. R. Zeldenrust, J. A. Lust, R. A. Kyle, L. 
Bergsagel and S. V. Rajkumar (2012). "Trisomies in multiple myeloma: impact on survival in patients 
with high-risk cytogenetics." Blood 119(9): 2100-2105. 
Kumar, S. K., W. I. Bensinger, T. M. Zimmerman, C. B. Reeder, J. R. Berenson, D. Berg, A. M. Hui, N. 
Gupta, A. Di Bacco, J. Yu, Y. Shou and R. Niesvizky (2014). "Phase 1 study of weekly dosing with the 
investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma." Blood 
124(7): 1047-1055. 
Kumar, S. K., W. I. Bensinger, T. M. Zimmerman, C. B. Reeder, J. R. Berenson, D. Berg, A. M. Hui, N. 
Gupta, A. Di Bacco, J. Yu, Y. Shou and R. Niesvizky (2014). "Weekly dosing of the investigational oral 
proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma: results from a phase 1 study." 
Blood. 
Kumar, S. K., J. G. Berdeja, R. Niesvizky, S. Lonial, J. P. Laubach, M. Hamadani, A. K. Stewart, P. Hari, 
V. Roy, R. Vescio, J. L. Kaufman, D. Berg, E. Liao, A. Di Bacco, J. Estevam, N. Gupta, A. M. Hui, V. 
Rajkumar and P. G. Richardson (2014). "Safety and tolerability of ixazomib, an oral proteasome inhibitor, 
in combination with lenalidomide and dexamethasone in patients with previously untreated multiple 
myeloma: an open-label phase 1/2 study." Lancet Oncol 15(13): 1503-1512. 
Kumar, S. K., A. Dispenzieri, M. Q. Lacy, M. A. Gertz, F. K. Buadi, S. Pandey, P. Kapoor, D. Dingli, S. 
R. Hayman, N. Leung, J. Lust, A. McCurdy, S. J. Russell, S. R. Zeldenrust, R. A. Kyle and S. V. 
Rajkumar (2013). "Continued improvement in survival in multiple myeloma: changes in early mortality 
and outcomes in older patients." Leukemia. 
Kumar, S. K., J. H. Lee, J. J. Lahuerta, G. Morgan, P. G. Richardson, J. Crowley, J. Haessler, J. Feather, 
A. Hoering, P. Moreau, X. LeLeu, C. Hulin, S. K. Klein, P. Sonneveld, D. Siegel, J. Blade, H. 
Goldschmidt, S. Jagannath, J. S. Miguel, R. Orlowski, A. Palumbo, O. Sezer, S. V. Rajkumar and B. G. 
Durie (2012). "Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs 
and bortezomib: a multicenter international myeloma working group study." Leukemia : official journal 
of the Leukemia Society of America, Leukemia Research Fund, U.K 26(1): 149-157. 
Kumar, S. K., J. R. Mikhael, F. K. Buadi, D. Dingli, A. Dispenzieri, R. Fonseca, M. A. Gertz, P. R. 
Greipp, S. R. Hayman, R. A. Kyle, M. Q. Lacy, J. A. Lust, C. B. Reeder, V. Roy, S. J. Russell, K. E. D. 
Short, A. K. Stewart, T. E. Witzig, S. R. Zeldenrust, R. J. Dalton, S. V. Rajkumar and P. L. Bergsagel 
(2009). "Management of Newly Diagnosed Symptomatic Multiple Myeloma: updated Mayo Stratification 
of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Guidelines." Mayo Clinic Proceedings 
84(12): 1095-1110. 
Kumar, S. K., S. V. Rajkumar, A. Dispenzieri, M. Q. Lacy, S. R. Hayman, F. K. Buadi, S. R. Zeldenrust, 
D. Dingli, S. J. Russell, J. A. Lust, P. R. Greipp, R. A. Kyle and M. A. Gertz (2008). "Improved survival 
in multiple myeloma and the impact of novel therapies." Blood 111(5): 2516-2520. 
Lopez-Anglada, L., N. C. Gutierrez, J. L. Garcia, M. V. Mateos, T. Flores and J. F. San Miguel (2010). 
"P53 deletion may drive the clinical evolution and treatment response in multiple myeloma." Eur J 
Haematol 84(4): 359-361. 


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Mikhael, J. R., D. Dingli, V. Roy, C. B. Reeder, F. K. Buadi, S. R. Hayman, A. Dispenzieri, R. Fonseca, 
T. Sher, R. A. Kyle, Y. Lin, S. J. Russell, S. Kumar, P. L. Bergsagel, S. R. Zeldenrust, N. Leung, M. T. 
Drake, P. Kapoor, S. M. Ansell, T. E. Witzig, J. A. Lust, R. J. Dalton, M. A. Gertz, K. Stewart, S. V. 
Rajkumar, A. Chanan-Khan and M. Q. Lacy (2013). "Management of Newly Diagnosed Symptomatic 
Multiple Myeloma: Updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) 
Consensus Guidelines 2013." Mayo Clin Proc 88(4): 360-376. 
Neri, A., L. Baldini, D. Trecca, L. Cro, E. Polli and A. T. Maiolo (1993). "p53 gene mutations in multiple 
myeloma are associated with advanced forms of malignancy." Blood 81(1): 128-135. 
Palumbo, A., S. Bringhen, T. Caravita, E. Merla, V. Capparella, V. Callea, C. Cangialosi, M. Grasso, F. 
Rossini, M. Galli, L. Catalano, E. Zamagni, M. T. Petrucci, V. De Stefano, M. Ceccarelli, M. T. 
Ambrosini, I. Avonto, P. Falco, G. Ciccone, A. M. Liberati, P. Musto, M. Boccadoro and G. Italian 
Multiple Myeloma Network (2006). "Oral melphalan and prednisone chemotherapy plus thalidomide 
compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised 
controlled trial." Lancet 367(9513): 825-831. 
Richardson, P. G., R. Baz, M. Wang, A. J. Jakubowiak, J. P. Laubach, R. D. Harvey, M. Talpaz, D. Berg, 
G. Liu, J. Yu, N. Gupta, A. Di Bacco, A. M. Hui and S. Lonial (2014). "Phase 1 study of twice-weekly 
dosing of investigational oral proteasome inhibitor ixazomib in patients with relapsed and/or refractory 
multiple myeloma." Blood. 
Saha, M. N., H. Jiang and H. Chang (2010). "Molecular mechanisms of nutlin-induced apoptosis in 
multiple myeloma: evidence for p53-transcription-dependent and -independent pathways." Cancer Biol 
Ther 10(6): 567-578. 
Saha, M. N., H. Jiang, J. Jayakar, D. Reece, D. R. Branch and H. Chang (2010). "MDM2 antagonist 
nutlin plus proteasome inhibitor velcade combination displays a synergistic anti-myeloma activity." 
Cancer Biol Ther 9(11): 936-944. 
Siegel, R., D. Naishadham and A. Jemal (2013). "Cancer statistics, 2013." CA Cancer J Clin 63(1): 11-30. 
Stuhmer, T. and R. C. Bargou (2006). "Selective pharmacologic activation of the p53-dependent pathway 
as a therapeutic strategy for hematologic malignancies." Cell Cycle 5(1): 39-42. 
Stuhmer, T., M. Chatterjee, M. Hildebrandt, P. Herrmann, H. Gollasch, C. Gerecke, S. Theurich, L. 
Cigliano, R. A. Manz, P. T. Daniel, K. Bommert, L. T. Vassilev and R. C. Bargou (2005). "Nongenotoxic 
activation of the p53 pathway as a therapeutic strategy for multiple myeloma." Blood 106(10): 3609-
3617. 
Tiedemann, R. E., N. Gonzalez-Paz, R. A. Kyle, R. Santana-Davila, T. Price-Troska, S. A. Van Wier, W. 
J. Chng, R. P. Ketterling, M. A. Gertz, K. Henderson, P. R. Greipp, A. Dispenzieri, M. Q. Lacy, S. V. 
Rajkumar, P. L. Bergsagel, A. K. Stewart and R. Fonseca (2008). "Genetic aberrations and survival in 
plasma cell leukemia." Leukemia 22(5): 1044-1052. 
Xiong, W., X. Wu, S. Starnes, S. K. Johnson, J. Haessler, S. Wang, L. Chen, B. Barlogie, J. D. 
Shaughnessy, Jr. and F. Zhan (2008). "An analysis of the clinical and biologic significance of TP53 loss 
and the identification of potential novel transcriptional targets of TP53 in multiple myeloma." Blood 
112(10): 4235-4246. 


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Appendix I 
ECOG Performance Status 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair. 
5 
Dead 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982. 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
From http://www.ecog.org/general/perf stat.html 
 
 




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Appendix III Drug Classification Guide 
 
Class 
Generic name 
Other Names 
Alkylators 
 
 
 
Cyclophosphamide 
Cytoxan 
 
 
Melphalan 
Alkeran 
 
 
Carmustine 
BCNU 
 
 
Busulphan 
Myleran 
 
 
Chlorambucil 
 
 
 
Cisplatin 
 
 
 
Dacarbazine 
 
 
 
Ifosfamide 
 
 
 
Lomustine 
CCNU 
 
 
Mecholorethamine 
Nitrogen mustard 
 
 
Procarbazine 
 
 
 
 
 
 
Antimetabolites 
 
 
 
Asparaginase 
 
 
 
Chlorodeoxyadenosine 
2-CDA 
 
 
Cytabarine 
Cytosar-U 
Tarabine 
 
Deoxycorormycin 
 
 
 
Floxuridine 
 
 
 
Fludarabine 
 
 
 
Flurouracil 
 
 
 
Hydroxyurea 
 
 
 
Mercaptopurine 
 
 
 
Methotrexate 
 
 
 
Thioguanine 
 
 
 
Thiotepa 
 
 
 
 
 
 
Anthracyclines/Antibiotics 
 
 
 
Bleomycin 
 
 
 
Dactinomycin 
 
 
 
Daunorubicin 
 
 
 
Doxorubicin 
Adriamycin 
 
 
Pegylated doxorubicin 
Doxyl 
 
 
Idarubicin 
 
 
 
Mitomycin 
 
 
 
Mitoxantrone 
 
 
 
 
 
 
Bisphosphonates 
 
 
 
Zoledronic acid 
Zometa 
 
 
Pamidronate 
Aredia 
 
 
 
 
 
Corticosteroids 
 
 
 
Prednisone 
 
 
 
Methylprednisolone 
Solumedrol 
 
 
Dexamethasone 
Decadron 
Dex 
 
 
 
 
 
 
 
 


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IMiDs (immune modulatory drugs) 
 
 
 
Thalidomide 
Thalidomid 
 
 
Lenalidomide 
Revlimid 
CC-5013 
 
Interferon 
 
 
 
Pomalidomide 
Pomalyst 
 
 
Levamisole 
 
 
 
 
 
 
Proteasome inhibitors 
 
 
 
Bortezomib 
Velcade 
 
 
Carfilzomib 
Kyprolis 
 
 
Ixazomib 
Ninlaro 
MLN9708 
 
Oprozomib 
 
 
 
 
 
 
Topoisomerases 
 
 
 
Etoposide 
VP-16 
 
 
 
 
 
 
 
 
 
Taxanes 
 
 
 
Paclitaxel 
Taxol 
 
 
Docetaxel 
Taxotere 
 
 
 
 
 
 
 
 
 
Monoclonal Antibodies 
 
 
 
Anti-SLAMF7 
Elotuzumab 
 
 
Anti-38 
Daratumumab 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vinca Alkyloid 
 
 
 
Vinblastine 
 
 
 
Vincristine 
 
 
 
Vindestine 
 
 
 
Vinorelbine 
 
 
 
 
 
 
 
 


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Appendix IV Cockcroft-Gault Equation 
 
For males: 
 
Creatinine Clearance = (140-age[years] × weight [kg]) 
OR 
(140–age[years] × weight [kg]) 
72 × (serum creatinine[mg/dL]) 
0.81 × (serum creatinine[μmol/L]) 
 
 
For females: 
 
Creatinine Clearance = 0.85 (140-age[years] × weight [kg])  OR 
0.85 (140-age[years] × weight [kg]) 
72 × (serum creatinine[mg/dL]) 
0.81 × (serum creatinine[μmol/L]) 
 
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16(1):31-41. 


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Appendix V 
MC1582 Model Consent 
MC1582 Model Consent Form 
*NOTES FOR LOCAL INVESTIGATORS:  
• 
The goal of the informed consent process is to provide people with sufficient information for making 
informed choices. The informed consent form provides a summary of the clinical study and the 
individual’s rights as a research participant. It serves as a starting point for the necessary exchange 
of information between the investigator and potential research participant. This template for the 
informed consent form is only one part of the larger process of informed consent. For more 
information about informed consent, review the “Recommendations for the Development of Informed 
Consent Documents for Cancer Clinical Trials” prepared by the Comprehensive Working Group on 
Informed Consent in Cancer Clinical Trials for the National Cancer Institute. The website address 
for this document is http://cancer.gov/clinicaltrials/understanding/simplification-of-informed-consent-
docs/ 
• 
A blank line, __________, indicates that the local investigator should provide the appropriate 
information before the document is reviewed with the prospective research participant.  
• 
Instructions and examples for informed consent authors are in [italics]. Remember to remove these 
items before finalizing your consent form. 
• 
The language should be written in 6th grade language. When proofreading the consent form, ask 
yourself if an average 6th grader would understand the study after reading this form. 
• 
Suggestion for Local Investigators: An NCI pamphlet explaining clinical trials is available for your 
patients. The pamphlet is entitled: “If You Have Cancer…What You Should Know about Clinical 
Trials.” This pamphlet may be ordered on the NCI website at https://cissecure.nci.nih.gov/ncipubs/ or 
call 1-800-4-CANCER (1-800-422-6237) to request a free copy. 
• 
Optional feature for Local Investigators: Reference and attach drug sheets, pharmaceutical 
information for the public, or other material on risks. Check with your local IRB regarding review of 
additional materials. 
*These notes for investigators are instructional and should not be included in the informed consent form 
given to the prospective research participant.  
 
RESEARCH PARTICIPANT CONSENT AND PRIVACY AUTHORIZATION FORM 
 
Study Title: Phase 1 / 2 trial of idasanutlin in combination with ixazomib and dexamethasone 
in patients with 17p-deleted relapsed multiple myeloma 
 
IRB#:  
{Insert local IRB number here} 
 
Principal Investigator: {Insert name of local investigator here} 
 
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. 
 


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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. 
 
 
CONTACT INFORMATION 
 
You can contact … 
At … 
If you have questions or about … 
Principal 
Investigator: 
Insert local PI Name 
 
Study Team Contact: 
Insert local contact 
here 
 
Phone: 
Insert local telephone 
 
Phone: 
Insert local telephone 
 
Address: 
Insert local address 
 
 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 
Institutional Review 
Board (IRB)/Research 
Ethics Board (REB) 
Phone: 
Insert IRB/REB 
telephone 
 
Toll-Free: 
 
 Rights of a research participant 
 


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You can contact … 
At … 
If you have questions or about … 
Research Subject 
Advocate 
(The RSA is 
independent of the 
Study Team) 
Phone: 
Insert local telephone 
 
 
E-mail: 
 
 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 
Research Billing 
Insert local telephone 
 Billing or insurance related to this 
research study 
 
Other Information: 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Website will not include information that can identify you. At most, the 
Website will include a summary of the results. You can search this Website at any time. 
 
 
 
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 type of 
blood cancer called “multiple myeloma” that requires treatment. In addition, your myeloma cells 
have a particular abnormality in the chromosomes that makes your multiple myeloma harder to 
treat. 
 
About 53 people will take part in this research study. 
 
 
 
2. 
Why is this research study being done? 
 
 
This research study is being done to see if the combination of two new drugs will allow better 
control of multiple myeloma where the cancer cells have lost a part or all of a chromosome 
(chromosome 17), a situation that is difficult to treat with the current standard treatment. 
 
In this study, you will be treated with a combination of two drugs called ixazomib and 
idasanutlin. It is thought that ixazomib will interfere with the process of protein breakdown in the 
multiple myeloma cells. Idasanutlin can make the myeloma cells more sensitive to treatment 
with other drugs like ixazomib, by masking the effect of the lost chromosome. The combination 
of drugs used in this study are considered investigational, which means they have either not been 
approved by the Food and Drug Administration (FDA) for routine clinical use or for the use 
described in this study. This study is being done to find out what effects (good and bad) the 


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combination of ixazomib and idasanutlin with dexamethasone has on you and your multiple 
myeloma. 
 
 
 
3. 
Information you should know 
 
 
Who is Funding the Study? 
 
Takeda/Millennium Pharmaceuticals and Roche Pharmaceuticals are funding the study. 
Takeda/Millennium and Roche will pay the Multiple Myeloma Research Foundation/Multiple 
Myeloma Research Consortium (MMRF/MMRC) to cover costs related to running the study. 
 
Information Regarding Conflict of Interest: 
 
Your doctor may be referring you to this study and if your doctor is also an Investigator in this 
study, he or she has a conflict by having two sets of interests (your well-being, and the scientific 
conduct of the study). If you are uncomfortable with your doctor working with you as part of this 
research study, but still wish to participate in the research, you may request to work with a 
different member of the research team. 
 
 
 
4. 
How long will you be in this research study? 
 
 
You will be in the study for approximately three years. You will be in the study for as long as 
your multiple myeloma is responding to the treatment and you are not having side effects that 
cannot be managed. 
 
 
 
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 tests and 
procedures. These tests and procedures are part of regular care for multiple myeloma: 
 
Prior to Registration 
• Physical exam including complete medical history, height, weight and vital signs (blood 
pressure, heart rate, pulse, etc.) 
• ECOG performance status (assessment of your ability to carry out daily activities) 
• Routine blood and urine tests 
• Skeletal survey (X-ray or low dose whole body CT) 


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• Electrocardiogram (ECG) 
• Chest x-ray 
• Pregnancy test 
• Bone marrow aspirate and biopsy 
 
As part of this study, you will also have the following tests and procedures. 
• Research blood tests (less than 2 tablespoons)  – these will be drawn at the same time as 
your clinical care 
• Research samples (bone marrow and blood) – these samples will be from the bone 
marrow aspirate and biopsy done for your clinical care 
 
Every Cycle Pre-treatment 
• Routine blood and urine tests 
• Physical exam including medical history, weight and vital signs 
• ECOG performance status (assessment of your ability to carry out daily activities) 
• Medication diary 
 
If you are a female of childbearing potential, you will need to have a blood or urine pregnancy 
test done weekly for the first four weeks of the study and every 28 days while on therapy with 
ixazomib and/or idasanutlin. In addition, you will need a pregnancy testing until 90 days after 
your last dose of ixazomib. 
 
End of Cycle 4 
• Bone marrow aspirate and biopsy for clinical care to see how your disease is responding 
to treatment 
• Research samples (bone marrow and blood) – taken at the same time as the clinical bone 
marrow aspirate and biopsy 
 
End of Treatment 
• Physical exam including medical history, weight and vital signs 
• ECOG performance status (assessment of your ability to carry out daily activities) 
• Routine blood and urine tests 
• Medication diary 
• Bone marrow aspirate and biopsy  
• Research samples (bone marrow and blood) – taken at the same time as the clinical bone 
marrow aspirate and biopsy 
 
 
 


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6. 
What are the possible risks or discomforts from being in this research 
study? 
 
 
You may have side effects while on the study. Everyone taking part in the study will be watched 
carefully for any side effects. However, doctors don’t know all the side effects that may happen. 
Side effects may be mild or very serious. Your health care team may give you medicines to help 
lessen side effects. In some cases, side effects can be serious, long lasting, or may never go 
away. 
 
You should talk to your study doctor about any side effects that you have while taking part in the 
study. 
 
As with any medication, allergic reactions are a possibility. 
 
Potential discomforts and risks of ixazomib 
Based on early studies of ixazomib, it is possible to predict some of the discomforts and risks. 
The data suggest that the potential risks of ixazomib are likely to be manageable if monitored 
and treated. However, risks could become serious and potentially life-threatening. It is possible 
that ixazomib may cause side effects that were not seen in animal studies or yet seen in patients. 
The following side effects might be seen. 
 
Common risks of ixazomib (events occurring greater than 20% of the time) 
• Feeling sick to your stomach (nausea) 
• Throwing up (vomiting) 
• Loose stools (diarrhea) 
• Constipation 
• Feeling tired or weak 
• 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)  
• Fever 
• Infection including shingles 
• Skin rash 
• Swelling of extremities 
• Numbness and tingling (also known as peripheral neuropathy) 
 


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Less likely risks of ixazomib (events occurring less than or equal to 20% of the time) 
• Decreased appetite (not feeling hungry, not wanting to eat) 
• Cough 
• Joint pain 
• Abdominal pain or distension 
• Difficulty sleeping 
• Back pain 
• Shortness of breath 
• Upper respiratory tract infection  
• Sensation of lightheadedness or vertigo (spinning sensation) (dizziness) 
• Blood chemical imbalance (electrolyte imbalance) – as seen on a blood test 
• Headache 
• Excessive or abnormal loss of body fluids (dehydration) 
 
Rare risks of ixazomib (events occurring less than 2-3% of the time) 
• Low or high blood pressure 
• A painful blistery red rash that is confined to one side of the body, similar to chicken pox 
(shingles - herpes zoster) 
• 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 
• 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 
 
Rare but serious risks of ixazomib 
• Life threatening severe skin rash 
• Abnormal heart rhythms 
• Worsening of your heart function (congestive heart failure) 
• Disorders of your lungs that could be serious enough to result in death 
• Liver failure 


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• 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 – may require hospitalization to resolve 
• 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) 
 
Progressive multifocal leukoencephalopathy (PML) has been reported with ixazomib in an 
oncology patient who had previously received a medication associated with PML. PML is a rare, 
serious infection of the brain that is caused by a virus. Persons with a weakened immune system 
may develop PML. PML can result in death or severe disability. It is not known whether 
ixazomib may have contributed to the development PML in this patient. 
 
Ixazomib should not be taken if you have ever had a serious allergic reaction to boron or boron 
containing products. 
 
Potential discomforts and risks of idasanutlin 
 
Likely risks of idasanutlin (events occurring greater than 20% of the time) 
• Diarrhea 
• Nausea 
• Vomiting 
• Decreased appetite 
• Fatigue 
• Decreased platelet counts 
• Fever 
• Low white blood cell count with or without fever (neutropenia) 
• Low levels of potassium in blood 
• Asthenia (weakness) 
• Anemia 
• Abdominal pain 
• Constipation 


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• Chest pain 
• Dry skin 
• Pruritus (itchy skin) 
• Dry eyes 
• Increased blood sugar levels 
• Myalgia (muscle pain) 
• Flushing 
• Increased risk of bleeding  
 
Less likely risks of idasanutlin (events occurring less than 20% of the time) 
•  
• Cough 
• Swelling of extremities 
• Headache 
• Hypomagnesaemia (low level of magnesium in the blood) 
• Hypophosphatemia (low level of phosphorus in the blood) 
• Shortness of breath 
• Back pain 
• Decreased levels of minerals in blood  
• Dizziness 
• Dry mouth 
• Altered taste 
• Chills 
• Insomnia 
• Skin rash 
• Mouth sores 
• Nose bleeds 
• Infections (that can be severe at times) 
• Pneumonia 
• Dehydration 
• Weight loss 
• Abnormal liver test 
• Low blood pressure 
• Difficulty sleeping 
 
Rare but serious risks of idasanutlin (events occurring less than 2-3% of the time) 
• Blood clots in lungs 
• Abnormal heart rhythm 
• Liver damage 
• Sepsis (Life threatening infections) 
• Tumor lysis syndrome (a condition where rapid destruction of tumor cells lead to 
abnormal mineral levels in the blood and kidney failure) 
• Heart failure 
 


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OTHER RISKS 
 
Standard of Care Risks 
 
Additionally, you might also have side effects or discomforts that are not listed in this form. 
Some side effects are not yet known, and every risk or side effect cannot be predicted. You may 
experience unexpected side effects or be at risk for symptoms, illnesses, and/or complications 
that could not be predicted. Tell your study doctor or study staff right away if you have any 
problems. 
 
Many side effects go away shortly after the study drugs are 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. 
 
Your doctor will discuss the risks of biopsies, X-rays, scans, and blood and urine testing, as these 
tests and procedures are part of your standard clinical care. 
 
Blood Samples 
Blood samples will be taken using a needle from a vein in your arm during the study. The taking 
of a blood sample may cause some discomfort and bruising, and there is a potential for infection. 
Other risks, although rare, include dizziness and fainting. The maximum amount of blood that 
will be taken at any study visit is about 42 mL (less than 3 tablespoons). 
 
Blood loss from taking research samples and the side effects of the study drug may cause anemia 
(low red blood cell count). Anemia may make you feel tired. Some people may need iron 
supplements to compensate for the blood loss resulting from the procedures done during this 
study. Please make sure that you discuss this issue with the study doctor or your personal doctor. 
 
Non-Physical Risks 
You may lose time at work or home and spend more time in the hospital or study doctor’s office 
than usual. 
 
BIRTH CONTROL, DANGERS OF PREGNANCY AND BREASTFEEDING 
 
You must not get pregnant while in this study. If you are or become pregnant, there may be 
unknown risks to the baby. If you may be able to have children, you will be given a pregnancy 
test at screening, and if the result is positive, you will not be able to be in the study. If you are 
sexually active, and able to have children, you and your partner must use two (2) highly effective 
forms of birth control throughout the study and for 90 days after your last dose of study drugs.  
 
Acceptable non-hormonal birth control methods include:  
• 
Total sexual abstinence. Abstinence must be for the total duration of the study i.e. from when 
you sign the informed consent form (ICF) until 90 days after the last dose of study drug 


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• 
Male sexual partner who has undergone a vasectomy plus male condom with spermicide. 
(You will need to confirm that your partner’s sperm was tested after the vasectomy procedure 
and that he was confirmed to be sterile.) 
• 
Tubal occlusion plus male condom with spermicide  
• 
Intrauterine Device (IUD) plus male condom with spermicide 
 
Acceptable hormonal methods include:  
• 
Etonogestrel implants (e.g., Implanon®, Norplan®) plus male condom with spermicide 
• 
Normal and low dose combined oral pills plus male condom with spermicide 
• 
Norelgestromin/ethinyl estradiol (EE) transdermal system plus male condom with spermicide 
• 
Intravaginal device (e.g., EE and etonogestrel) plus male condom with spermicide 
• 
Cerazette® (desogestrel) plus male condom with spermicide. (Cerazette® is currently the 
only highly efficacious progesterone based pill.) 
 
You should discuss with your study doctor which birth control methods are considered 
acceptable. 
 
A pregnancy test can be wrong. If you become pregnant or think you may be pregnant during the 
study, stop taking study capsules and contact the study doctor’s office immediately. You will be 
asked to withdraw from the study. You must not be breast-feeding an infant during the study. 
The study drug may cause unforeseeable risk to a breastfed baby. The study doctor must follow 
up and document the course and the outcome of all pregnancies, even if you withdraw from the 
study or if the study has finished. 
 
FOR MEN 
If not sexually abstinent, men who have female partner(s) of childbearing potential should not 
father a child.  Men must also agree to use an effective method of birth control before starting 
study treatment, during study treatment, and for 90 days following drug completion.  In addition, 
men should not donate semen or sperm while on study or for 90 days following drug completion.  
  
Many side effects go away shortly after the idasanutlin and ixazomib are 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. 
 
 
 
7. 
Are there reasons you might leave this research study early? 
 
 
Taking part in this research study is voluntary. You may decide to stop at any time. You should 
tell the Principal Investigator if you decide to stop and you will be advised whether any 
additional tests may need to be done for your safety.  
 


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In addition, the Principal Investigator or Mayo Clinic may stop you from taking part in this study 
at any time: 
• If it is in your best clinical interest 
• If you do not follow the study procedures 
• If the study is stopped 
 
If you leave this research study early, or are withdrawn from the study, no more information 
about you will be collected; however, information already collected about you in the study may 
continue to be used. 
 
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study. 
 
 
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. 
 
 
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. The study will not offer free medical care 
or payment for any bad side effects from taking part in this study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form. 
 
 
 
9. 
What are the possible benefits from being in this research study? 
 
 
This study may or may not make your health better. While doctors hope that taking idasanutlin 
and ixazomib with dexamethasone will help, there is no proof of this outcome yet. We do know 
that the information from this study will help doctors learn more about multiple myeloma. This 
information could help future cancer patients with a similar condition compared to yours. 
 
 
 


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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: 
• Taking part in another study 
• Getting treatment or care for your cancer without being in a study 
• Getting no treatment 
 
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?  
 
 
The study drugs, ixazomib and idasanutlin, will be given to you at no cost. You and/or your 
insurance might also have to pay for other drugs or treatments given to help control side effects. 
 
You won’t need to pay for tests and procedures which are done just for this research study. These 
tests and procedures are: 
o Research testing on your blood and bone marrow 
o Research testing on any biopsy tissue 
 
You and/or your insurance will need to pay for all tests and procedures that are part of this 
research study. 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 listed in the Contacts section. If you wish, 
arrangements can be made for you to speak with someone in Patient Financial Services about 
these costs. 
 
If you have billing or insurance questions call Research Billing at the telephone number 
provided in the Contact Information section of this form. 
 
 
 
 
12. 
Will you be paid for taking part in this research study? 
 
 
You will not be paid for your participation in this study. 
 


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Your participation in this research study may contribute to the development of commercial 
products from which Takeda Pharmaceuticals/Millennium Pharmaceuticals, Inc., Roche 
Pharmaceuticals, Inc., or others, may derive an economic benefit. You will have no rights to any 
patents or discoveries arising from this research, and you will receive no economic benefit. 
 
 
 


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13. 
What will happen to your samples? 
 
 
Your samples will be sent to the Sponsor (Mayo Clinic). The Sponsor can use your samples for research 
purposes only as described in the research study and this consent form. Your sample will be sent to the 
Sponsor in a coded format, which protects your identity. Mayo Clinic may destroy the sample at any time 
without telling you. 
 
 
 
14. 
How will your privacy and the confidentiality of your records be protected? 
 
 
[Note to Local Investigators: The NCI has recommended that HIPAA regulations be addressed 
by the local institution. The regulations may or may not be included in the informed consent form 
depending on local institutional policy.] 
 
We will do our best to make sure that the personal information in your medical record will be 
kept private. However, we cannot guarantee total privacy. Your personal information may be 
given out if required by law. If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used.  
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
• 
Mayo Clinic, the sponsor of this study 
• 
The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), involved in keeping research safe for people 
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. 
 
[Note to Local Investigators: The NCI has recommended that the above paragraph, 
containing language required by the FDA, be added in order to be in compliance with 
the Final Rule by the effective date of 07Mar2012.] 
 
 
 


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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 
 
 
Local IRB changes to this document are allowed. Sections “What are the risks of the research 
study” or “What other choices do I have if I don’t take part in this research study?” should 
always be used in their entirety if possible. Editorial changes to these sections may be made as 
long as they do not change information or intent. If the institutional IRB insists on making 
deletions or more substantive modifications to these sections, they may be justified in writing by 
the investigator and approved by the IRB. Under these circumstances, the revised language and 
justification must be forwarded to the Mayo Clinic Cancer Center Clinical Research Office 
) for approval before a patient may be registered to this study. 
 
Consent forms will have to be modified for each institution as it relates to where information 
may be obtained on the conduct of the study or research subject. This information should be 
specific for each institution.