Study of Bendamustine and IXAZOMIB (MLN9708) Plus Dexamethasone in Relapsed/Refractory Multiple Myeloma

OVERVIEW: This Phase I/II study is designed to first identify doses of MLN9708 and
bendamustine that are associated with an acceptable adverse event profile when delivered
together in 28-day cycles. Additionally, the study aims to assess the efficacy of the
combination in patients with relapsed/refractory multiple myeloma. Responders (stable disease
or more),will continue to receive up to eight cycles total in the absence of further
progressive disease.

OVERVIEW OF THE DOSE ESCALATION/DE-ESCALATION THAT WAS USED: This study aims to assess the
combination's efficacy in patients with relapsed/refractory multiple myeloma. Responders
(stable disease or more),will continue to receive up to eight cycles total in the absence of
further progressive disease. The dose of MLN9708 will be fixed at 4 mg, days 1, 8 and 15.
Dexamethasone administered as 40 mg oral on Days 1, 8, 15 of each 28 day cycle. The dose of
MLN9708 will be fixed at 4 mg, days 1, 8 and 15. Dexamethasone administered as 40 mg oral on
Days 1, 8, 15 of each 28 day cycle. Three doses of bendamustine will be evaluated (Dose 1: 70
mg/m2, days 1 and 2; Dose 2: 80 mg/m2. days 1 and 2; and Dose 3: 90 mg/m2, days 1 and 2).
NOTE:

PHASE 1 DESIGN: A 3+3 design was employed. At each dose, three patients were initially
evaluated. When no dose limiting toxicities were observed, the bendamustine dose was
increased.

PHASE 2 DESIGN: Design for Phase II portion of study: The MTD or a recommended phase 2 dose
(RP2D) for the combination (80mg/m2 bendamustine) was identified in 2016, the plan is to
treat additional patients at that dose to assess efficacy and response to treatment. The
investigators plan to enroll 19 patients (including those treated at the MTD in Phase I).

INCLUSION CRITERIA:

1. Male or female patients 18 years or older.

2. Voluntary written consent must be given before performance of any study related
procedure not part of standard medical care, with the understanding that consent may
be withdrawn by the patient at any time without prejudice to future medical care.

3. Female patients who:

- Are postmenopausal for at least one year before the screening visit, OR

- Are surgically sterile, OR

- If they are of childbearing potential, agree to practice two 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, ovulation, symptothermal,
post-ovulation methods] and withdrawal are not acceptable methods of
contraception.)

Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree
to one of the following:

- Agree to practice effective barrier contraception during the entire study
treatment period and through 90 days after the last dose of study drug, OR

- 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, postovulation methods] and withdrawal are not acceptable methods
of contraception.)

4. Patients must have have histologically or cytologically confirmed symptomatic Multiple
Myeloma, who are non-seponsive to or ineligible for autologous stem cell transplant,
and who progress after prior exposure to proteasome inhibitor (bortezomib,
carfilzomib) and IMID (lenalidomide or pomalidomide or thalidomide); and
refractory/progressing to at least one of these agents and must meet at least one of
the following parameters of measurable disease:

- Measurable levels of monoclonal protein (M protein): > 1 g/dL of IgG or IgM
M-protein or > 0.5 g/dL IgA or IgD M protein on serum protein electrophoresis OR
> 200 mg/24h of free light chain proteinuria on a 24 hour urine protein
electrophoresis which must be obtained within 4 weeks prior to registration OR >
10 mg/dL involved free light chain on serum free light chain testing with an
abnormal kappa:lambda light chain ratio.

- Patients with lytic bone disease, defined as at least one lytic lesion that can
be accurately measured in at least one dimension.

5. Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance
status 0, 1, or 2.

6. Patients are eligible after autologous or allogeneic stem cell transplantation.
Allogeneic transplantation can be enrolled only if they have no ongoing transplant
related side effects.

7. Patients must be at least 2 weeks from major surgery, radiation therapy, participation
in other investigational trials and have recovered from clinically significant
toxicities of these prior treatments

8. Patients must meet the following clinical laboratory criteria:

- Absolute neutrophil count (ANC) ≥ 1,000/mm3 and platelet count ≥ 75,000/mm3.
Platelet transfusions or G-CSF can be used to help patients meet eligibility
criteria but are not allowed within 3 days before study enrollment.

- Total bilirubin < 1.5 x the upper limit of the normal range (ULN), , OR, dDirect
bilirubin within normal limits (WNL), when total bilirubin is >>< 1.5 x the ULN.

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 x ULN.

- Calculated creatinine clearance ≥ 30 mL/min.

EXCLUSION CRITERIA

Patients meeting any of the following exclusion criteria are not to be enrolled in the
study:

1. Female patients who are lactating or have a positive serum pregnancy test during the
screening period.

2. Failure to have fully recovered (ie, ≤ Grade 1 toxicity) from the reversible effects
of prior chemotherapy except for peripheral neuropathy, which is addressed in
exclusion criteria no. #14.

3. Major surgery within 14 days before enrollment.

4. Radiotherapy within 14 days before enrollment. If the involved field is limited
(single disease focus not involving pelvis and involving <36 Gy radiation), 7 days
will be considered a sufficient interval between treatment and administration of
Ixazomib provided hematologic inclusion parameters are met.

5. Central nervous system involvement.

6. Infection requiring systemic antibiotic therapy or other serious infection within 14
days before study enrollment.

7. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled
hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure,
unstable angina, or myocardial infarction within the past 6 months.

8. Systemic treatment, within 14 days before the first dose of IXAZOMIB, with strong
inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of
CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole,
nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin,
carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort.

9. Ongoing or active systemic infection, active hepatitis B or C virus infection, or
known human immunodeficiency virus (HIV) positive.

10. Any serious medical or psychiatric illness that could, in the investigator's opinion,
potentially interfere with the completion of treatment according to this protocol.

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

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

13. Diagnosed or treated for another malignancy where the expected surbvival is less than
two years will be excluded. Patients with nonmelanoma skin cancer or carcinoma in situ
of any type are not excluded if they have undergone complete resection.

14. Patient has ≥ Grade 2 peripheral neuropathy, or Grade 2 with pain on clinical
examination during the screening period.

15. Participation in other clinical trials, including those with other investigational
agents not included in this trial, within 30 days of the start of this trial and
throughout the duration of this trial.

16. Patients that have previously been treated with IXAZOMIB, or participated in a study
with IXAZOMIB whether treated with IXAZOMIB or not.

17. Patients with a history of severe chronic obstructive pulmonary disease requiring
ongoing oxygen support or those with a resting oxygen saturation <92% on room air
irrespective of the cause.