MLN9708 (Ixazomib) in Combination With Panobinostat and Dexamethasone in Multiple Myeloma

The primary objective of this study is to define the tolerability and safety of MLN9708
(ixazomib) administered on a day 1,8,15 every 28 day schedule up to 4mg in combination with
fixed doses of panobinostat and dexamethasone in patients with relapsed or refractory
myeloma.

The secondary objectives of this study are to assess response and clinical benefit response
rates according to international uniform response criteria and adapted EBMT criteria,
respectively. And to assess progression-free survival (PFS) and overall survival (OS).

Inclusion Criteria:

- Ability to provide written informed consent obtained prior to participation in the
study and any related procedures being performed

- Patients must carry a diagnosis of symptomatic multiple myeloma according to
international myeloma working group criteria and have relapsed or refractory disease
according to international uniform response criteria and must have previously received
therapy with a proteasome inhibitor and an IMiD™

- Must have measurable disease defined as any of the following: Serum m-spike ≥ 1g/dL,
24 h urine m-spike of at least 200mg/d, involved serum free light chains ≥ 100mg/L
with abnormal serum free light chain ratio, bone marrow plasma cells of at least 30%

- ECOG PS ≤ 2

- No gastro-intestinal condition, that in the opinion of the treating physician or the
principal investigator significantly limits oral absorption

- No serious uncontrolled coexisting medical condition

- Patients must meet the following laboratory criteria:

- ANC ≥ 1.0 x 10^9/L without use of pegfilgrastim in the preceding 21 days and
without non-pegylated G-CSF or GM-CSF within 7 days prior to study entry

- Hemoglobin ≥ 8 g/dl (may be after transfusion of packed red blood cells or use of
erythropoiesis stimulating agents)

- Platelets ≥ 70x 10^9/L without platelet transfusion 7 days prior to study entry

- AST and ALT ≤ 2.5 x ULN

- Serum bilirubin ≤ 1.5 x ULN

- Serum potassium ≥ LLN and serum magnesium ≥ LLN (electrolyte levels may be
achieved with repletion or other supportive medications like potassium sparing
diuretics)

- Creatinine clearance ≥ 30 mL/min according to Cockroft-Gault formula

- Clinically euthyroid. Note: Patients are permitted to receive thyroid hormone
supplements to treat underlying hypothyroidism.

- Baseline MUGA or ECHO must demonstrate LVEF ≥ 45%

- Women of childbearing potential (WOCBP) must have a negative serum pregnancy test
within 7 days prior to start of study treatment

- Male patients, even if surgically sterilized (i.e., status post vasectomy), have to
either:

- Agree to practice effective barrier contraception during the entire study
treatment period and through 4 months after the last dose of study treatment, OR

- Must also adhere to the guidelines of any treatment-specific pregnancy prevention
program, if applicable, OR

- Agree to practice true abstinence when this is in line with the preferred and
usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation,
symptothermal, post-ovulation methods] and withdrawal are not acceptable methods
of contraception.

- Female patients have to fulfill one of the following:

- Be postmenopausal for at least 1 year before the Screening visit, OR

- Be surgically sterile, OR

- If of childbearing potential, agree to practice 2 effective methods of
contraception, at the same time, from the time of signing the informed consent
through 90 days after the last dose of study treatment

- Oral contraceptives are generally metabolized by CYP3A4. Since the induction
potential of panobinostat to induce CYP3A4 is unknown, patients who are using
oral contraceptives as a method of contraception, and are sexually active, should
use another effective contraceptive method, AND Must also adhere to the
guidelines of any treatment-specific pregnancy prevention program, if applicable,
OR

- Agree to practice true abstinence when this is in line with the preferred and
usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation,
symptothermal, post-ovulation methods] and withdrawal are not acceptable methods
of contraception.)

- At least 7 days must have passed since the last treatment with lenalidomide,
pomalidomide, thalidomide, proteasome inhibitors, or low dose cyclophosphamide (up to
50mg daily), at least 21 days must have passed since the last treatment with
daratumumab, elotuzumab, investigational therapy and most conventional chemotherapy
including cyclophosphamide above 50mg per dose, bendamustine, doxorubicin, cisplatin,
and etoposide; and at least 35 days since the last treatment with melphalan.

Exclusion Criteria:

- Prior anti-cancer treatment with MLN9708 (ixazomib), HDAC, DAC, HSP90 inhibitors or
valproic acid

- Prior participation in a randomized controlled study that included MLN9708 (ixazomib)
in one of the treatment arms independent of whether assigned to MLN9708 (ixazomib) or
not

- Patients who will need valproic acid for any medical condition during the study or
within 5 days prior to first panobinostat treatment

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

- Impaired cardiac function or clinically significant cardiac diseases, including any
one of the following:

- History or presence of sustained ventricular tachyarrhythmia. (Patients with a
history of atrial arrhythmia are eligible)

- Any history of ventricular fibrillation or torsade de pointes

- Bradycardia defined as HR< 50 bpm. Patients with pacemakers are eligible if HR ≥
50 bpm.

- Screening ECG with a QTcF > 470 msec (QTcF=QT/3√RR). If potassium or magnesium
blood levels are below normal limits, consider repeating ECG after correction of
these electrolytes

- Right bundle branch block + left anterior hemiblock (bifascicular block)

- Patients with myocardial infarction or unstable angina ≤ 6 months prior to
starting study drug

- Other clinically significant heart disease (e.g., CHF NY Heart Association class
III or IV , uncontrolled hypertension, history of labile hypertension, or history
of poor compliance with an antihypertensive regimen)

- Impairment of GI function or GI disease that may significantly alter the swallowing
absorption of panobinostat and MLN9708

- Patients with diarrhea > CTCAE (version 4.03) grade 2

- Patient has ≥ Grade 3 peripheral neuropathy, or ≥ Grade 2 with pain on clinical
examination during the screening period.

- Patients with known metastasis of malignant plasma cells to the central nervous system
(if not suspected nonspecific testing is required)

- Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled
diabetes or active or uncontrolled infection) including abnormal laboratory values,
that could cause unacceptable safety risks or compromise compliance with the protocol

- Patients using medications that have a relative risk of prolonging the QT interval or
inducing torsade de pointes if treatment cannot be discontinued or switched to a
different medication prior to starting study drug. If an alternative medication that
does not risk QT prolongation can safely be used in the opinion of the treating
physician and the treatment is changed to that medication, the patient may be
enrolled.

- Patients who have not passed the nadir of bone marrow suppression from previous
anti-myeloma therapy yet. If in doubt, serial CBCs with differential should be
obtained.

- The corticosteroids prednisone and dexamethasone may be continued until the day before
treatment start if all related adverse events are controlled at CTCAE version 4.03
grade ≤ 1.

- Patients who have received radiation therapy to more than half of the pelvis or more
than half of the spine within ≤ 2 weeks prior to starting study treatment; or who have
not yet recovered from side effects of such therapies.

- Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or
who have not recovered from side effects of such therapy

- Systemic treatment, within 14 days before study enrollment, 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.

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

- Concurrent diagnosis of another malignancy if either systemic treatment or surgery is
expected to be required within 2 years from study entry.

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

- Patients with any significant history of non-compliance to medical regimens or
unwilling or unable to comply with the instructions given to him/her by the study
staff.

- Infection requiring systemic antibiotic therapy or other serious infection within 14
days before study enrollment unless the patient is felt to have fully recovered and
any antibiotics that are continued are either beta lactam antibiotics or are
specifically allowed on study.

- Participation in other clinical trials, including those with other investigational
agents not included in this trial, within 21 days of the start of this trial and
throughout the duration of this trial.