Ixazomib as a Replacement for Carfilzomib and Bortezomib for Multiple Myeloma Patients

This is a phase 1/2, intra-patient, multicenter, open-label and non-randomized study to
evaluate the efficacy and safety of ixazomib as a replacement for bortezomib or carfilzomib
among multiple myeloma (MM) patients who have failed proteasome inhibitor (PI)-containing
combination regimens. Patients will receive ixazomib once a week in place of bortezomib or
carfilzomib in combination with an alkylating agent (melphalan or cyclophosphamide),
anthracycline (pegylated doxorubicin [PLD]), immunomodulatory agent (lenalidomide,
pomalidomide), ascorbic acid and/or a glucocorticosteroid (dexamethasone, prednisone or
methylprednisolone) administered using the same dose(s) and schedule(s) as the last
PI-containing regimen that the patients had received and failed. The total number of
different prior bortezomib- or carfilzomib-containing regimens that will be evaluated is 10,
reflecting those commonly used in the community as follows:

- bortezomib + melphalan + prednisone

- bortezomib + cyclophosphamide + ascorbic acid

- bortezomib + cyclophosphamide + dexamethasone

- bortezomib + PLD + dexamethasone

- bortezomib + dexamethasone

- carfilzomib + dexamethasone

- bortezomib + lenalidomide + dexamethasone

- bortezomib + pomalidomide + dexamethasone

- carfilzomib + lenalidomide + dexamethasone

- carfilzomib + pomalidomide + dexamethasone

This study will enroll 60 patients who are refractory to a bortezomib- or
carfilzomib-containing combination regimen, as demonstrated by progressive disease (PD) while
being treated, or who have relapsed within 8 weeks from the last dose of bortezomib or
carfilzomib in their last PI-containing combination regimen.

Ixazomib will replace bortezomib or carfilzomib using the same PI-containing regimen the
patients failed.The study will consist of: 1) a screening period; 2) up to eight 28-day
treatment cycles; 3) a maintenance period; 4) a final assessment to occur 28 days after the
end of the last treatment cycle; and 5) a follow-up period.

Ixazomib will be administered PO at 4 mg on Days 1, 8 and 15 of a 28-day cycle to patients
enrolled in seven regimens (bortezomib + melphalan + prednisone, bortezomib + dexamethasone,
carfilzomib + dexamethasone, bortezomib + lenalidomide + dexamethasone, bortezomib +
pomalidomide + dexamethasone, carfilzomib + lenalidomide + dexamethasone, carfilzomib +
pomalidomide + dexamethasone). Subjects on those regimens receiving 4 mg of ixazomib from the
beginning of the trial will continue to do so for the length of the study, unless they suffer
from adverse events requiring dose reductions. For the other three regimens, bortezomib +
cyclophosphamide + dexamethasone, bortezomib + cyclophosphamide + ascorbic acid, and
bortezomib + PLD + dexamethasone, the MTD for ixazomib is unknown and intra-patient dose
escalation will be performed to determine the specific MTD for each of them. For these three
regimens, ixazomib will be administered on Days 1, 8 and 15 of a 28-day cycle at a starting
dose of 3 mg in Cycle 1, and then intra-patient dose-escalation will proceed to 4 mg in Cycle
2. All other agents will be administered at the same schedule and dose intensity as those of
the last PI-containing treatment the patient failed.

Key Inclusion Criteria:

1. Male or female patients 18 years or older

2. Patients must have a diagnosis of MM, based on standard criteria as follows:

- Major criteria:

1. plasmacytomas on tissue biopsy

2. bone marrow plasmacytosis (greater than 30% plasma cells)

3. monoclonal immunoglobulin spike on serum electrophoresis IgG greater than
3.5 g/dL or IgA greater than 2.0 g/dL; kappa or lambda light chain excretion
greater than 1 g/day on 24 hour urine protein electrophoresis

- Minor criteria:

1. bone marrow plasmacytosis (10% to 30% plasma cells)

2. monoclonal immunoglobulin present but of lesser magnitude than given under
major criteria

3. lytic bone lesions

4. normal IgM less than 50 mg/dL, IgA less than 100 mg/dL, or IgG less than 600
mg/dL

Any of the following sets of criteria will confirm the diagnosis of multiple myeloma:

- any 2 of the major criteria

- major criterion 1 plus minor criterion 2, 3, or 4

- major criterion 3 plus minor criterion 1 or 3

- minor criteria 1, 2, and 3, or 1, 2, and 4

3. Currently has progressive MM that has previously progressed or is currently
progressing while receiving or within 8 weeks of receiving bortezomib or carfilzomib
as part of a combination treatment. MM patients that demonstrate refractory disease,
as defined below, are both eligible for enrollment provided they fulfill the other
eligibility criteria:

• Patients are refractory to a bortezomib or carfilzomib combination regimen, when
they progress while currently receiving a bortezomib or carfilzomib combination
treatment, or within 8 weeks of its last dose. Patients are considered relapsed, when
they progress between 8 and 12-weeks from their last dose of bortezomib or carfilzomib
as part of a bortezomib or carfilzomib combination therapy. Prior treatment with four
days or less of a total of 400 mg of prednisone (or an equivalent potency of another
steroid) for MM will not be considered a regimen.

4. Patients that were on bortezomib-containing regimens must have been administered at
least 4 doses of a minimum of 1.0 mg/m2 in no more than 28-days cycles. Subjects must
have received at least one cycle meeting this definition and have shown PD to be
considered eligible

5. Patients that were on carfilzomib-containing regimens must have received at least 6
doses of at least 27 mg/m2 in no more than 28 days per cycle. Subjects must have
received at least one cycle meeting this definition and have shown PD to be considered
eligible

6. Progressed from one of the specific bortezomib- or carfilzomib-containing regimens as
listed on page 51. Although bortezomib- and carfilzomib-containing combination
regimens that are otherwise identical except for the PI result in the same ixazomib
regimen, they will be enrolled separately so that safety/efficacy can be separately
determined, thereby allowing comparisons based on the prior PI that subjects were
exposed to as part of the regimen that they failed (carfilzomib vs. bortezomib)

7. Patient may have received a carfilzomib- or bortezomib-containing regimen at any time
and may have received other non-proteasome inhibitor-containing intervening treatments

Key Exclusion Criteria:

1. Patient has been diagnosed with:

1. Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy,
monoclonal protein (M protein) and skin changes (POEMS) syndrome.3

2. Primary amyloidosis

3. Plasma cell leukemia

4. Severe hypercalcemia, i.e., serum calcium = 12 mg/dL (3.0 mmol/L) corrected for
albumin

2. Diagnosed or treated for another malignancy within 3 years before study enrollment or
previously diagnosed with another malignancy and have any evidence of residual
disease. Patients with non-melanomatous skin cancer or carcinoma in situ of any type
are not excluded if they have undergone complete resection.

3. Impaired cardiac function or clinically significant cardiac diseases, including
myocardial infarction within 6 months prior to enrollment, New York Heart Association
(NYHA) Class II or greater heart failure, uncontrolled angina, clinically significant
pericardial disease, severe uncontrolled ventricular arrhythmias, echocardiogram or
multigated acquisition scan (MUGA) evidence of left ventricular ejection fraction
(LVEF) below institutional normal within 28 days prior to enrollment,
electrocardiographic evidence of acute ischemia or active conduction system
abnormalities. Prior to study entry, any ECG abnormality at Screening has to be
documented by the investigator as not medically relevant

4. Patient has peripheral neuropathy grade 3 or higher or Grade 2 with pain on clinical
examination during the screening period

5. Patient has received the following prior therapy:

1. Chemotherapy within 21 days of enrollment (6 weeks for nitrosoureas)

2. Corticosteroids (>10 mg/day prednisone or equivalent) within 21 days of
enrollment

3. Immunotherapy or antibody therapy as well as thalidomide, pomalidomide,
lenalidomide, arsenic trioxide, carfilzomib, or bortezomib within 21 days before
enrollment

6. Known allergy to any of the study medications, their analogues, or excipients in the
various formulations of any agent

7. Known GI disease or GI procedure that could interfere with the oral absorption or
tolerance of ixazomib including difficulty swallowing