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modifications for prolonged qtc)

The criteria for dose modifications for study drug-related toxicity are detailed in table 7-4.  
Table 7-4 Criteria for dosing delays, dose-reductions, and re-initiation of treatment due to study drug-related toxicity (excluding QT prolongation)  
| Worst Toxicity                                                                                                                                                                                                                                              | Dose Modification Guidelines                                               |             |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------|-------------|
| CTCAE Grade* unless otherwise specified (Value)                                                                                                                                                                                                             | At any time during a cycle of  therapy (including intended day of  dosing) |             |
| HEMATOLOGICAL TOXICITIES Thrombocytopenia Grade 4 (< 25 x 109 /L)                                                                                                                                                                                           | Temporarily                                                                | discontinue |
| panobinostat and MLN9708 dosing  until platelets have increased to> 50  x 109 /L, then reduce dose of one of  these drugs by one level per cycle  starting with panobinostat until  panobinostat is at 10mg, then  alternate with ixazomib dose  reductions |                                                                            |             |  
| Confidential                                              |                                                                            |             |             |
|-----------------------------------------------------------|----------------------------------------------------------------------------|-------------|-------------|
| Worst Toxicity                                            | Dose Modification Guidelines                                               |             |             |
| CTCAE Grade* unless otherwise specified (Value)           | At any time during a cycle of  therapy (including intended day of  dosing) |             |             |
| Neutropenia (ANC)                                         | Grade 4 (ANC < 0.5 x 109 /L)                                               | Temporarily | discontinue |
| panobinostat and MLN9708 dosing  and consider use of G-CSF or GMCSF until the ANC has increased to  > 0.5 x 109 /L , then reduce dose of  one of these drugs by one level per  cycle starting with panobinostat  until panobinostat is at 10mg, then  alternate with ixazomib dose reductions. If neutropenia was the  only reason for dose reduction,  consider maintaining the same dose  level with prophylactic use of G-CSF  or GM-CSF in the next cycle when  neutrophil counts decrease below 1 x  109 /L.                                                           |                                                                            |             |             |
| Febrile neutropenia (ANC < 1.0 x 109 /L, fever ≥  38.5°C) | Temporarily                                                                | discontinue |             |
| panobinostat and MLN9708 dosing  and consider use of G-CSF or GMCSF until fever resolved and ANC ≤  grade 2, then reduce dose of one of  these drugs by one level per cycle  starting with panobinostat until  panobinostat is at 10mg, then  alternate with ixazomib dose  reductions.                                                           |                                                                            |             |             |  
| Worst Toxicity                                                                                                                                                                                                                                                                                                   | Dose Modification Guidelines                                               |             |              |            |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------|-------------|--------------|------------|
| CTCAE Grade* unless otherwise specified (Value)                                                                                                                                                                                                                                                                  | At any time during a cycle of  therapy (including intended day of  dosing) |             |              |            |
| NON-HEMATOLOGICAL TOXICITIES CARDIAC Cardiac - Prolonged QT interval**                                                                                                                                                                                                                                           | Please refer to Section 7.5.4.                                             |             |              |            |
| PERIPHERAL NEUROPATHY Grade 1-2 with clinically significant impact on                                                                                                                                                                                                                                            | Consider                                                                   | holding     | ixazomib     |            |
| quality of life                                                                                                                                                                                                                                                                                                  | (MLN9708)                                                                  | and         | restarting   | at         |
| reduced                                                                                                                                                                                                                                                                                                          | level                                                                      | upon        | satisfactory |            |
| improvement                                                                                                                                                                                                                                                                                                      |                                                                            |             |              |            |
| Grade 3                                                                                                                                                                                                                                                                                                          | Hold                                                                       | ixazomib    | (MLN9708)    | and        |
| restart                                                                                                                                                                                                                                                                                                          | at                                                                         | reduced     | level        | upon       |
| resolution to Grade ≤ 1 or baseline.                                                                                                                                                                                                                                                                             |                                                                            |             |              |            |
| Grade 4                                                                                                                                                                                                                                                                                                          | Permanently discontinue ixazomib  (MLN9708)                                |             |              |            |
| RASH Grade 2                                                                                                                                                                                                                                                                                                     | Symptomatic recommendations as  per section 7.6                            |             |              |            |
| GASTROINTESTINAL Diarrhea                                                                                                                                                                                                                                                                                        | Grade                                                                      | 2           | (4-6         | stools/day |
| over baseline, etc.) despite  the use of optimal  antidiarrheal medications                                                                                                                                                                                                                                      | Temporarily                                                                | discontinue |              |            |
| panobinostat and MLN9708 dosing  until resolved to ≤ grade 1, or  baseline, then restart at unchanged  dose levels at the first occurrence. If  this adverse event recurs at grade 2 in  subsequent cycles reduce dose by  one level alternating between  panobinostat and MLN9708, starting  with panobinostat. |                                                                            |             |              |            |
| Grade 3 (≥ 7 stools/day over  baseline, etc.) despite the  use of optimal antidiarrheal  medications                                                                                                                                                                                                             | Temporarily                                                                | discontinue |              |            |
| panobinostat and MLN9708 dosing  until resolved to ≤ grade 1, or  baseline, then reduce dose by one  level alternating between  panobinostat and MLN9708, starting  with panobinostat.                                                                                                                           |                                                                            |             |              |            |  
| Confidential                                                                                                                                                                                                                                               |                                                                                 |                   |             |        |    |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------|-------------------|-------------|--------|----|
| Worst Toxicity                                                                                                                                                                                                                                             | Dose Modification Guidelines                                                    |                   |             |        |    |
| CTCAE Grade* unless otherwise specified (Value)                                                                                                                                                                                                            | At any time during a cycle of  therapy (including intended day of  dosing)      |                   |             |        |    |
| Grade                                                                                                                                                                                                                                                      | 4                                                                               | (life-threatening |             |        |    |
| consequences,  hemodynamic                                                                                                                                                                                                                                 | collapse,                                                                       |                   |             |        |    |
| etc.)                                                                                                                                                                                                                                                      | despite                                                                         | the               | use         | of     |    |
| optimal                                                                                                                                                                                                                                                    | antidiarrheal                                                                   |                   |             |        |    |
| medications                                                                                                                                                                                                                                                | Take patient off study.                                                         |                   |             |        |    |
| Nausea/vomiting                                                                                                                                                                                                                                            | Grade 1 & 2 not requiring  treatment or controlled  using standard anti-emetics | Maintain          | dose        | levels | of |
| panobinostat,                                                                                                                                                                                                                                              | MLN9708,                                                                        | and               |             |        |    |
| dexamethasone.                                                                                                                                                                                                                                             |                                                                                 |                   |             |        |    |
| Grade 3 or 4 vomiting or  Grade 3 nausea that cannot  be controlled despite the  use of standard anti-emetics                                                                                                                                              | Temporarily                                                                     | discontinue       |             |        |    |
| panobinostat and MLN9708 dosing  until resolved to ≤ grade 1, or  baseline, then reduce dose by one  level alternating between  panobinostat and MLN9708, starting  with panobinostat.                                                                     |                                                                                 |                   |             |        |    |
| FATIGUE Fatigue                                                                                                                                                                                                                                            | Grade                                                                           | 3                 | (fatigue    | not    |    |
| relieved by                                                                                                                                                                                                                                                | rest                                                                            | limiting          |             |        |    |
| self-care activities of daily  life)                                                                                                                                                                                                                       | Temporarily                                                                     | discontinue       |             |        |    |
| panobinostat dosing until resolved to  ≤ grade 2 (fatigue not relieved by rest  limiting instrumental activities of  daily life), or baseline, then reduce  dose by one level alternating  between panobinostat and  MLN9708, starting with  panobinostat. |                                                                                 |                   |             |        |    |
| HEPATIC Total Bilirubin                                                                                                                                                                                                                                    | Grade 3-4 (> 3 x ULN)                                                           | Temporarily       | discontinue |        |    |
| panobinostat and MLN9708 dosing  until resolved to ≤ grade 2, or  baseline, then reduce dose by one  level alternating between  panobinostat and MLN9708, starting  with panobinostat.                                                                     |                                                                                 |                   |             |        |    |  
| Worst Toxicity                                                                                                                                                                                                                                                                                                                                                                                | Dose Modification Guidelines                                                                                                 |             |             |      |    |    |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------|-------------|-------------|------|----|----|
| CTCAE Grade* unless otherwise specified (Value)                                                                                                                                                                                                                                                                                                                                               | At any time during a cycle of  therapy (including intended day of  dosing)                                                   |             |             |      |    |    |
| AST/SGOT, ALT/SGPT                                                                                                                                                                                                                                                                                                                                                                            | > 5-10 x ULN                                                                                                                 | Temporarily | discontinue |      |    |    |
| panobinostat and MLN9708 dosing  until resolved to ≤ grade 1 (or ≤ grade  2 if liver infiltration with myeloma is  present), or baseline, then:  If resolved within 7 days, then:  restart panobinostat and  MLN9708 at unchanged dose  levels If resolved in more than 7 days, then  reduce dose by one level alternating  between panobinostat and  MLN9708, starting with  panobinostat. |                                                                                                                              |             |             |      |    |    |
| > 10 x ULN                                                                                                                                                                                                                                                                                                                                                                                    | Temporarily                                                                                                                  | discontinue |             |      |    |    |
| panobinostat dosing until resolved to  ≤ grade 1, or baseline, then reduce  dose by one level alternating  between panobinostat and  MLN9708, starting with  panobinostat.                                                                                                                                                                                                                    |                                                                                                                              |             |             |      |    |    |
| Other NON-HEMATOLOGICAL TOXICITIES Grade 2 with clinically significant impact on quality                                                                                                                                                                                                                                                                                                      | Consider holding study drug(s) felt                                                                                          |             |             |      |    |    |
| of life                                                                                                                                                                                                                                                                                                                                                                                       | to be responsible and restarting at  reduced level and/or with improved  supportive measures upon  satisfactory improvement. |             |             |      |    |    |
| Grade 3                                                                                                                                                                                                                                                                                                                                                                                       | Hold                                                                                                                         | study       | drug(s)     | felt | to | be |
| responsible and restart at reduced  dose level upon resolution to Grade  ≤ 1 or baseline.                                                                                                                                                                                                                                                                                                     |                                                                                                                              |             |             |      |    |    |
| Grade 4                                                                                                                                                                                                                                                                                                                                                                                       | Strongly                                                                                                                     | consider    | permanently |      |    |    |
| discontinuing study drug(s) felt to be  responsible but resuming at reduced  dose upon resolution to < grade 1 or  baseline is allowed if clinical  judgment suggests net benefit from  continued treatment.                                                                                                                                                                                  |                                                                                                                              |             |             |      |    |    |  
Worst Toxicity CTCAE Grade* unless otherwise specified (Value)
Dose Modification Guidelines At any time during a cycle of therapy (including intended day of dosing)
All dose modifications should be based on the worst preceding toxicity. * Common Terminology Criteria for Adverse Events (CTCAE Version 4)
** It is critical that electrolyte abnormalities be followed closely and corrected prior to dosing
*** See also concomitant medication Section 7.7
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7.5.4 dose modifications for prolonged

All cardiac events should be treated as per the local standard of care and referred to a specialist if clinically indicated. Initial assessments will be made by the treating physician based on the QTc calculated by the ECG machine according to the Bazett formula (QTcB=QT/√RR). Any panobinostat dosing or withholding decisions will only be made after calculation of the QTcF
according to the following formula QTcF=QT/3√RR by trained research nurses or the principal investigator. If a patient cannot be dosed due to prolonged QTcF for more than 7 days since last dose, patient should be discontinued from study.  
Table 7-5 Dose modifications for prolonged QTcF  
| ECGs                 | to                | be                                                                                                      |
|----------------------|-------------------|---------------------------------------------------------------------------------------------------------|
| performed            | at                |                                                                                                         |
| specified time point | Abnormality Noted | Dose Modification Guideline - At any time during a cycle of therapy  (including intended day of dosing) |
| Dose modifications are based on local readings of the average QTcF* of triplicate ECGs. *QTcF: Heart rate corrected QT interval using the Fredericia formula: ���� = �� (����)/√�� � (��� Pre-panobinostatdose on cycle 1, day 1: 3 ECGs separated by  5-10 minutes,  obtained prior to  panobinostat dosing. Average QTcF > 470  Check and correct the patient's serum  msec potassium, magnesium, and calcium  immediately, as well as evaluate con-meds that can prolong (or is known to be associated  with) QTc interval. Repeat 3 pre-panobinostat-dose ECGs. If the 3 pre-panobinostat-dose ECGs: Do not meet criteria again, discontinue  patient from study. Do meet criteria for dosing; administer study  drug treatment.                      |                   |                                                                                                         |  
| ECGs                 | to                | be                                                                                                      |
|----------------------|-------------------|---------------------------------------------------------------------------------------------------------|
| performed            | at                |                                                                                                         |
| specified time point | Abnormality Noted | Dose Modification Guideline - At any time during a cycle of therapy  (including intended day of dosing) |
| Dose modifications are based on local readings of the average QTcF* of triplicate ECGs. *QTcF: Heart rate corrected QT interval using the Fredericia formula: ���� = �� (����)/√�� � (��� Pre-panobinostatdose on day 5, cycle  1, and on day 1 of  subsequent cycles: 3 ECGs separated by  5-10 minutes,  obtained prior to  panobinostat dosing Average QTcF: ≥ 481 msec to < 500  msec OR > 60 msec increase  from baseline  average Check and correct the patient's serum  potassium, magnesium, and calcium  immediately, as well as evaluate con-meds. Delay panobinostat dose at least 3 days, hold  MLN9708, and repeat 3 pre-panobinostatdose ECGs. If the repeat 3 pre-panobinostat-dose ECGs: Do not meet pre-panobinostat-dose ECG  criteria again, discontinue patient from study. Do meet pre-panobinostat-dose ECG criteria  for dosing and QT prolongation determined  to be related to study drug, resume study drug  treatment with a panobinostat dose reduction  of 5 mg. If however, it was determined that  the QT prolongation was secondary to  electrolyte abnormalities or con-meds,  continue at the same dose level upon  correction of the electrolyte imbalance or  discontinuation of the offending con-med.  Repeat ECGs - pre-panobinostat-dose (x3),  3-hours post-panobinostat-dose (x3), on the  next scheduled panobinostat dosing day. Pre-panobinostatdose on cycle 1, day  5 and on day 1 of  subsequent cycles: 3 ECGs separated by  5-10 minutes,  obtained prior to  panobinostat dosing Average QTcF ≥ 500  Check and correct the patient's serum  msec potassium, magnesium, and calcium  immediately. Discontinue patient from study therapy. If however, it was determined that the QT  prolongation was secondary to electrolyte  abnormalities or con-meds: Omit panobinostat and next MLN9708 dose.  On the next scheduled panobinostat dosing  day continue at the same dose level. Repeat  ECGs - pre-panobinostat-dose (x3), 3-hours  post-panobinostat-dose (x3), on the next  scheduled dosing day.CASE 4A13 A9 04/03/2017 59                      |                   |                                                                                                         |  
| ECGs                 | to                | be                                                                                                      |
|----------------------|-------------------|---------------------------------------------------------------------------------------------------------|
| performed            | at                |                                                                                                         |
| specified time point | Abnormality Noted | Dose Modification Guideline - At any time during a cycle of therapy  (including intended day of dosing) |
| Dose modifications are based on local readings of the average QTcF* of triplicate ECGs. *QTcF: Heart rate corrected QT interval using the Fredericia formula: ���� = �� (����)/√�� � (��� Post-panobinostat  dose on cycle 1, days  1 and 5: 3 ECGs separated by  5-10 minutes,  obtained 3 hours +/- 0.5 hours after  panobinostat dosing: Average QTcF ≥ 481 msec to < 500 msec OR > 60 msec increase  from baseline Check and correct the patient's serum  potassium, magnesium, and calcium  immediately, as well as evaluate con-meds. Monitor ECG hourly or by telemetry until  at least 2 consecutive hourly ECGs  performed at least 6 hours post dose show  QTcF < 481. Next scheduled panobinostat dosing day:  repeat 3 pre-panobinostat-dose ECGs. If these 3 pre-panobinostat-dose ECGs: Do not meet pre-panobinostat-dose ECG  criteria for dosing (average QTcF ≤ 480  msec), discontinue patient from study. Do meet pre-panobinostat-dose ECG criteria  for dosing (average QTcF ≤ 480 msec) and  QT prolongation determined to be related to  study drug, resume study drug treatment with a panobinostat dose reduction of 5 mg. If however, it was determined that the QT  prolongation was secondary to electrolyte  abnormalities or con-meds, continue at the  same dose level if responsible con-meds  could be stopped and any electrolyte  abnormalities are corrected. Repeat ECGs - pre-panobinostat-dose (x3), 3-hours postpanobinostat-dose (x3) on the next scheduled  dosing day.                      |                   |                                                                                                         |  
| ECGs                 | to                | be                                                                                                      |
|----------------------|-------------------|---------------------------------------------------------------------------------------------------------|
| performed            | at                |                                                                                                         |
| specified time point | Abnormality Noted | Dose Modification Guideline - At any time during a cycle of therapy  (including intended day of dosing) |
| Dose modifications are based on local readings of the average QTcF* of triplicate ECGs. *QTcF: Heart rate corrected QT interval using the Fredericia formula: ���� = �� (����)/√�� � (��� Average QTcF ≥ 500  Check and correct the patient's serum  msec potassium, magnesium, and calcium  immediately. Discontinue patient from study therapy and  monitor ECG hourly or by telemetry until at  least 2 consecutive hourly ECGs performed  at least 6 hours post dose show QTcF < 480. If however, it was determined that the QT  prolongation was secondary to electrolyte  abnormalities or con-meds: omit  panobinostat and MLN9708 dose. On the  next scheduled dosing day continue at the  same dose level. Repeat ECGs - prepanobinostat-dose (x3), 3-hours postpanobinostat-dose (x3), on the next  scheduled dosing day.                      |                   |                                                                                                         |
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7.6 management of clinical events

Mild infections may be treated with concurrent oral antibiotics of the beta-lactam class, with azithromycin or levofloxacin, or with other antibiotics taking possible pharmacokinetic interactions with panobinostat and MLN9708 into account. Infections that are associated with fever (temperature 38C on two consecutive measurements or one temperature of 38.5 C or higher) or with other concerning clinical signs or symptoms require holding all study drugs until the infection is controlled.
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nausea and/or vomiting

Standard anti-emetics, including 5-HT3 antagonists, are recommended for emesis occurring upon treatment initiation; prophylactic anti-emetics may also be considered. Dexamethasone should not be administered as an anti-emetic. Fluid deficits should be corrected before initiation of study drug and during treatment.
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diarrhea

Diarrhea should be managed according to standard clinical practice, including the administration of antidiarrheals once infectious causes are excluded. Fluid intake should be maintained to avoid dehydration. Fluid deficits should be corrected before initiation of treatment and during treatment.
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erythematous rash with or without

As with VELCADE, rash with or without pruritus has been reported with MLN9708, primarily at the higher doses tested. The rash may range from some erythematous areas to macular and/or small papular bumps that may or may not be pruritic over a few areas of the body or more generalized, or it may have been transient and resolved either spontaneously or with standard symptomatic measures such as oral or topical antihistamines. Prophylactic measures should also be considered if a patient develops a rash (e.g., using a thick, alcohol-free emollient cream on dry areas of the body). In the case of rash, the use of a topical or oral steroid (e.g., prednisone ≤ 10 mg per day or equivalent) is permitted. A rare risk is Stevens-Johnson Syndrome, a severe, life-threatening or deadly rash with skin peeling and mouth sores, which should be managed symptomatically according to standard medical practice.
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thrombocytopenia

Thrombocytopenia has been reported with MLN9708 and panobinostat. 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. MLN9708 administration should be modified as noted as per dose modification recommendations in Table 3-2 and Table 7-4 when thrombocytopenia occurs. Therapy can be reinitiated at a reduced level upon recovery of platelet counts.
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neutropenia

Neutropenia has been reported with MLN9708 and panobinostat. Blood counts should be monitored regularly as outlined in the protocol with additional testing obtained according to standard clinical practice. GM-CSF and G-CSF may be used to shorten neutropenic periods and to maintain dose level of study drugs if neutropenia is the only reason for dose reduction according to table Table 7-4 and at the discretion of the treating physician.
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fluid deficits

Dehydration should be avoided because MLN9708 and panobinostat may cause vomiting, diarrhea, and dehydration. Two cases of acute renal failure have been reported in patients treated at or above the MTD with IV administration of MLN9708. There has been no treatmentrelated renal failure reported in patients treated with PO MLN9708. Fluid deficits should be corrected before initiation of study drug and during treatment. Until further information is available, intake of NSAIDs while on this protocol should be avoided.
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hypotension

Symptomatic hypotension and orthostatic hypotension have been reported with MLN9708. Blood pressure should be closely monitored while the patient is on study treatment and fluid deficit should be corrected as needed, especially in the setting of concomitant symptoms such as nausea, vomiting, diarrhea, or anorexia. Patients taking medications and/or diuretics to manage their blood pressure (for either hypo- or hypertension) should be managed according to standard clinical practice, including considerations for dose adjustments of their concomitant medications during the course of the trial.
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posterior reversible encephalopathy syndrome

One case of posterior reversible encephalopathy syndrome (PRES) has been reported with MLN9708. While this case ultimately resolved, PRES has also been reported rarely with another proteasome inhibitor, VELCADE. PRES is characterized by headache, seizures and visual loss, as well as abrupt increase in blood pressure. Prompt diagnosis and initiation of antihypertensive and anticonvulsant therapy are important to prevent irreversible end-organ damage.
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7.6.1 study drug discontinuation

It will be documented whether or not each patient completed the clinical study. If for any patient either study treatment or observations were discontinued, the reason will be recorded in the source documents and within ONCORE. Patients will be informed that they have the right to withdraw from the study at any time for any reason, without prejudice to their medical care. The investigator also has the right to withdraw patients from the study for any of the following reasons: 1. Disease progression, this always requires removal from study 2. Adverse event(s) 3. Abnormal laboratory value(s) 4. Abnormal test procedure result(s) 5. For phase I patients only: Dosing delay of > 21 days (= unable to receive study therapy for 22 days including any therapy held during a cycle)
6. For phase I patients only: Delay of a cycle by > 14 days from the intended day of the next scheduled dose, counted from the start of the previous cycle.  
CASE 4A13 A9 04/03/2017 63
7. Protocol violation 8. Subject withdrew consent 9. Lost to follow-up 10. Administrative problems 11. New anti-myeloma therapy started 12. Study Termination 13. Death
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7.6.2 follow-up for toxicities

Patients whose treatment is interrupted or permanently discontinued due to a possibly studydrug related adverse event or abnormal laboratory value must be followed until resolution to CTCAE V 4.03 grade 2 or 30 days post last study drug administration, whichever comes first.  
If a patient requires a dose delay of > 14 days from the intended day of the next scheduled dose, then the patient must be discontinued from the study. All patients will be followed for adverse events and serious adverse events for at least 4 weeks following the last dose of any study drug.
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7.7 other concomitant medications

Patients must be instructed not to take any additional medications (including over-the-counter products) during the trial without prior consultation with the investigator. All medications taken within 30 days of screening should be recorded. If concomitant therapy must be added or changed, the reason and name of the drug/therapy should be recorded. In general, the use of any concomitant medication/therapies deemed necessary for the care of the patient are allowed, including IV bisphosphonates and drugs given prophylactically (e.g. antiemetics) with the following exceptions:
Any medications listed in Section 19 which may cause QTc prolongation or inducing torsades de pointes should not be used.  
Any medications that have the potential to alter serum electrolytes (e.g., diuretics) should be monitored very closely for electrolyte abnormalities as these can contribute to the risk of QT prolongation and ventricular arrhythmias.  
No other investigational therapy should be given to patients No anticancer agents other than the study medications administered as part of this study protocol should be given to patients. If such agents are required for a patient then the patient must first be withdrawn from the study.  
Leukocyte growth factors (e.g. G-CSF and GM-CSF) are not to be administered systematically but may be prescribed by the investigator for severe neutropenia if this is thought to be appropriate, see also for guidance under table 7-4..  
Medications known to be substrates of the isoenzyme CYP2D6 should be used with caution with panobinostat as panobinostat can inhibit isoenzyme CYP2D6 at low micromolar ranges. Please refer to Section 21 for the list of CYP2D6 substrates. .  
Concomitant use of CYP3A4 inhibitors with panobinostat should be used with caution due to a potential increase in panobinostat exposure during concomitant treatment with these drugs.
CASE 4A13 A9 04/03/2017 64  
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.
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7.7.1 summary of commonly used

While a heightened awareness about possible pharmacokinetic and pharmacodynamic interactions should be maintained with any medication used concomitantly with study drugs the following are generally considered safe due to lack of reported interaction or large therapeutic window despite possible interaction:
HT3 blockers (with caution, D/C if followed by QTcF prolongation), metoclopramide, and prochlorperazine Loperamide, diphenoxylate/atropine Azithromycin, levofloxacin, pefloxacin, ofloxacin, tosufloxacin, difloxacin, temafloxacin, fleroxacin, acrosoxacin, and nalidixic acid are allowed Acetaminophen and opioid analgesics other than methadone Regular orange juice and dihydropyridine calcium channel blockers (e.g. amlodipine, felodipine, nicardipine, nifedipine) are allowed IV bisphosphonates G-CSF, GM-CSF: Their use is allowed and should follow institutional practice and guidance outlined in table 7-4, alternative usage may be reviewed with Millennium and Novartis.  
Erythropoietin will be allowed in this study. Its use should follow published guidelines and/or institutional practice.  
Patients should be transfused with red cells and platelets as clinically indicated and according to institutional guidelines.  
Antiviral therapy such as acyclovir may be administered if medically appropriate.
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7.7.2 summary of prohibited concomitant

The following contains commonly used medications that should not be used during this study due to either pharmacokinetic interactions or pharmacodynamically based increased risk for adverse events. It is not inclusive. See Sections 19-21 for more information.  
Grapefruit or grapefruit juice and seville (sour) oranges (regular orange juice is allowed)
CASE 4A13 A9 04/03/2017 65  
Non-steroidal anti-inflammatory agents (NSAIDs) should be avoided if possible due to risk for kidney dysfunction in myeloma but if clinical judgement strongly argues for their use patients can remain on study while receiving NSAIDs Other antineoplastic agents Other investigational agents Aprepitant All Class IA antiarrhythmics: quinidine, procainamide, disopyramide, any other class IA antiarrhythmic drug All Class III antiarrhythmics: amiodarone, sotalol, bretylium, disopryramide, dofetilide, ibutilide, any other class III antiarrhythmic drug Calcium channel blockers: diltiazem, verapamil The following Antibiotics: Erythromycin, clarithromycin, telithromycin (azithromycin is allowed), enoxacin, sparfloxacin, ciprofloxacin, voriconazole, ketoconazole, and posaconazole Antipsychotics/antidepressants: thioridazine, mesoridazine, chlorpromazine, pimozide, fluvoxamine, nefazodone Antimalarials: halofantrine, chloroquine Miscellaneous drugs: arsenic trioxide, astemizole, bepridil, domperidone, levomethadyl, methadone, pentamidine, droperidol Strong inhibitors of CYP1A2: fluvoxamine, enoxacin, ciprofloxacin Strong inhibitors of CYP3A: clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, and posaconazole Strong CYP3A inducers: rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, and phenobarbital The dietary supplements St John's wort and Ginkgo biloba are not permitted.
CASE 4A13 A9 04/03/2017 66 The following procedures are prohibited during the study:  
Any antineoplastic treatment with activity against MM except for drugs in this treatment regimen.
Radiation therapy (the requirement for local radiation therapy generally indicates disease progression).Platelet transfusions can be given as clinically indicated but eligibility for starting a new cycle needs to be determined after at least 72 h without platelet transfusion and eligibility for inclusion in this trial needs to be determined after at least 7 days without platelet transfusion. Adjuvant hormone therapy for breast or prostate cancer.
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7.7.3 anti-coagulant therapy

Panobinostat and MLN9708 therapy is commonly associated with mild to moderate degree of thrombocytopenia. This may lead to an increase in the risk of bleeding with concomitant sodium warfarin (Coumadin®). It is recommended that patients who require anticoagulation therapy while on panobinostat therapy use low molecular weight heparin (LMWH). However, if the use of LMWH is not feasible, patients on sodium warfarin may continue such therapy while on study but for such patients, a close and frequent monitoring of the coagulation parameters, including PT/INR should be followed and they should be maintained within a therapeutic range. The dose of sodium warfarin may be adjusted as needed while on study.
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7.8 precautions and restrictions

Fluid and electrolyte deficits should be corrected before and throughout treatment.  
Nonsteroidal anti-inflammatory drugs (NSAIDs) risk for nephrotoxicity is increased in patients with multiple myeloma, underlying kidney dysfunction, and dehydration. NSAIDs should generally be avoided in patients with multiple myeloma, especially if other risk factors co-exist.
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7.9 contraception requirements

The effects of MLN9708 and panobinostat on human pregnancy or development of the embryo or fetus are unknown. Therefore, female patients participating in this study should avoid becoming pregnant, and male patients should avoid impregnating a female partner. Nonsterilized female patients of reproductive age and male patients should use effective methods of contraception through defined periods during and after study treatment as specified below.  
CASE 4A13 A9 04/03/2017 67 Female patients must meet the following eligibility criteria:
Are postmenopausal for at least 1 year before the screening visit, OR  
Are surgically sterile, OR Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, for at least 28 days before starting study drug through 90 days after the last dose of study treatment.  
o The 2 methods of reliable contraception must include 1 highly effective method and 1 additional effective (barrier) method. Females of childbearing potential must be referred to a qualified provider of contraceptive methods if needed. The following are examples of highly effective and additional effective methods of contraception:
Highly effective methods:
Intrauterine device (IUD)  
Hormonal (injections, implants)
Tubal ligation Partner's vasectomy
Additional effective methods:
Male condom  
Diaphragm Cervical Cap
Male patients, even if surgically sterilized (i.e., status post vasectomy), must meet the following eligibility criteria:
CASE 4A13 A9 04/03/2017 68 Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.),
OR  
Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study treatment if their partner is of childbearing potential, even if they have had a successful vasectomy.  
Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable.
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7.9.1 cyp2d6 substrates

In in vitro assays, panobinostat was shown to inhibit the cytochrome P450 isoenzyme CYP2D6 at low micromolar ranges, thereby suggesting a potential risk of drug-drug interactions with concomitant medications that are also metabolized by CYP2D6. A clinical drug-drug interaction study with dextromethorphan (a CYP2D6 probe drug) and panobinostat is currently ongoing in cancer patients. In the meantime, medications that are known to be CYP2D6 substrates should be used with caution when given concomitantly with panobinostat. Patients must be carefully monitored for signs of toxicity as a result of concomitant medication which may require dose titration or reduction of the CYP2D6 substrate as medically necessary. Please see Appendix 1 and refer to the following website: http://medicine.iupui.edu/flockhart/table.htm for a list of substrates of CYP2D6.
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7.9.2 drugs that can inhibit/induce

Panobinostat is metabolized in vitro by CYP3A4/5. A clinical drug-drug interaction study with ketoconazole and panobinostat has recently been completed. The less than 2-fold increase in panobinostat AUC upon co-administration with ketoconazole suggests that CYP3A contribution to the total clearance of panobinostat is low. The observed interaction is not considered clinically relevant, as panobinostat doses at least 2-fold greater than 20 mg (40 and 60 mg) have been safely administered in patients. CYP3A4 inhibitors should have no major impact on the exposure of panobinostat and may be co-administered when medically necessary.
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7.9.2.2 drugs that are potent

As it is with other medications that are metabolized by CYP3A4, clinical judgment is to be exercised when potent CYP3A4 inducers are concomitantly taken with panobinostat.
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7.10 treatment compliance

Records of study medication used, dosages administered, and intervals between visits will be recorded during the study. Drug accountability will be noted and patients will be asked to return all unused study medication.
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8 visit schedule and assessments

| Examinations                          | Screening   | Cycle 1    | Cycles 2 and   | Study   |        |    |
|---------------------------------------|-------------|------------|----------------|---------|--------|----|
| beyond                                | exit 8      |            |                |         |        |    |
| D-7 to D1                             | D1          | D5         | Weekly         | D 1     | Weekly |    |
| Informed consent                      | X           |            |                |         |        |    |
| Background information 1              | X           |            |                |         |        |    |
| Inclusion/exclusion criteria          | X           |            |                |         |        |    |
| Bone marrow examination  2            | X           |            |                |         |        |    |
| Skeletal survey 3                     | X           |            |                |         |        |    |
| Echocardiogram or MUGA  scan 3        | X           |            |                |         |        |    |
| Vital signs 4                         | X           | X          | X              | X       |        |    |
| History & Physical  examination       | X           | X          | X              | X       | X      |    |
| ECG 5                                 | X           | X          | X              | X5      |        |    |
| CBC/Diff                              | X           | X          | X              | X       | X10    | X  |
| PTT, INR                              | X           |            |                |         |        |    |
| CMP,, magnesium                       | X           | X          | X              | X       | X10    | X  |
| Response parameters                   |             |            |                |         |        |    |
| SPEP, 24h UPEP, sFLCs,                | X           | X          | X              |         |        |    |
| serum and urine IFE TSH, free T3, FTI | x           | Cycle  4X9 | X              |         |        |    |
| Pregnancy testing 6                   | X           | X          |                |         |        |    |
| Compliance review/drug  calendar 7    | X           | X          |                |         |        |    |  
* Unless noted otherwise all visits and assessments should occur on the scheduled day +/- 3 days but a new cycle may not begin unless ECG and electrolyte assessment has been completed within 24h prior to day one dosing and criteria are met for the start of a new cycle (7.4).  
1) Background information. The treating physician is responsible for comprehensive assessment of background information as it relates to eligibility for this trial. The following will be recorded on the CRFs: Year and month symptomatic myeloma was diagnosed, cytogenetic findings at diagnosis (karyotype, FISH, gene expression profile as available), beta 2 microglobulin, serum albumin, and LDH levels at diagnosis, number of prior therapies, and responses to prior therapies. Past medical history, past surgical history, and allergies as recorded in patient's charts 6 month prior to enrollment and all concomitant medications at the time of enrollment will also be recorded.  
2) Bone marrow examinations: In general this will only be done once at screening or within 28 days prior to study entry but for patients who appear to have reached a complete remission based on blood and urine studies it will be repeated for confirmation. Patients who have measurable disease only in the bone marrow will have bone marrow examinations after cycle 2 and at the end of the study. Additional bone marrow examinations may be obtained as clinically indicated. 3) Skeletal survey and left ventricular ejection fraction determination by Echocardiogram or MUGA scan: Within 28 days prior to study entry. 4) Vital sign assessment consists of height (first visit), pulse, blood pressure, respiration rate, temperature and weight. Blood pressure, pulse and respiration rate should be measured on patients after at least 3 minutes in the sitting position 5) ECGs:
On Screening: One ECG
On day 1 and 5 of cycle 1: Pre-dose: One ECG, Post-dose at 3 hours ± 0.5 hour: One ECG
On day 1 of cycle 2: Pre-dose: One ECG
Additional ECGs as detailed under 7.5.4 may be necessary if QTcF prolongation prevents dosing of panobinostat and MLN9708 or if felt clinically necessary for other reasons 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). All females of childbearing potential should complete a serum pregnancy test within 7 days prior to the administration of study drugs on day 1 of cycle 1. The pregnancy test should be repeated in week 1 of every cycle (except for cycle 1). 7) Compliance review / study calendar: Nurses review medication compliance based on study calendar patients fill out.  
8) Study exit: Visits and assessments at study exit should occur within 3 days prior and 7 days after the end of the previous cycle or within 7 days after the decision to remove the patient from study. If grade >
3 non-hematologic adverse events or grade 4 neutropenia or thrombocytopenia are present at study exit, the respective adverse events should be followed weekly until resolution to grade 2 for nonhematologic adverse events and grade 3 for neutropenia and thrombocytopenia or until 30 days from last treatment have elapsed.  
9) Thyroid function tests should be obtained at study entry, at about 3 months from study entry, ideally after the third 28-day cycle, whenever there is clinical suspicion for hypothyroidism, and at the completion of this study unless it has been obtained within 30 days prior to study exit. 10) Weekly CBC/diff, CMP, and magnesium until completion of cycle 2, then as clinically indicated
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8.1 efficacy / response assessments

Baseline assessments must occur within  7 days of protocol therapy initiation as indicated in Section 8, schedule of assessments. Response assessments include serum protein electrophoresis (SPEP), serum free light chains (sFLCs), 24 h urine protein electrophoresis with m-spike (24h UPEP), serum and urine immunofixation, and, for confirmation of complete remission and to monitor asecretory myeloma; bone marrow examinations. Efficacy assessments are scheduled to occur after each cycle except for bone marrow examinations which are done only for confirmation of complete remission (once) and in patients CASE 4A13 A9 04/03/2017 71 with measurable disease restricted to bone marrow plasma cell percentage, where bone marrow is obtained after cycle 2 and at study completion. All response categories require two consecutive blood and urine assessments (bone marrow biopsies do not need to be repeated) and no evidence for progressive or new bone lesions if radiographic studies were performed. Radiographic studies are not required for response assessment but should be obtained when there is clinical suspicion for progressive bone disease. The time point myeloma response parameters first fall into respective response levels is recorded as the time a response is achieved once a consecutive set of tests confirmed the response. For response categories > PR the confirmatory test may be obtained at any time but will generally be obtained at the start of the next cycle unless there is a clinical reason to obtain earlier; for MR consecutive tests have to confirm MR over a period of at least 6 weeks.  
| Complete response (CR)                                                                                                                                                                                                                                                                                | Negative immunofixation of serum and urine (or normal  sFLC ratio if the only measurable disease outside of the  bone marrow is by sFLCs) and disappearance of any soft  tissue plasmacytomas, and <5% plasma cells in bone  marrow                                                                                                                                                                                                                                                                                                                                                              |       |             |            |    |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------|-------------|------------|----|
| Stringent CR (sCR)                                                                                                                                                                                                                                                                                    | CR as defined above plus normal sFLC ratio and  absence of clonal cells in bone marrow                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | by    |             |            |    |
| immunohistochemistry or immunofluorescence                                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |       |             |            |    |
| Very good partial response (VGPR) Serum                                                                                                                                                                                                                                                               | and                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | urine | M-component | detectable | by |
| immunofixation but not on electrophoresis or  >90% or greater reduction in serum M-component plus  urine M-component <100mg per 24 h or >90% reduction  in the difference between involved and uninvolved serum  free light chains if this is the only measurable disease  outside of the bone marrow |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |       |             |            |    |
| Partial response (PR)                                                                                                                                                                                                                                                                                 | >50% reduction of serum M protein and reduction in 24- h urinary M protein by >90% or to <200mg per 24 h, if  the serum and urine M protein are unmeasurable, a >50%  decrease in the difference between involved and  uninvolved sFLC levels is required in place of the M  protein criteria, if the only measurable disease is in the  bone marrow, a >50% reduction in bone marrow plasma  cells is required, provided the baseline percentage was  >30%. In addition to the above criteria, if present at  baseline, a >50% reduction in the size of soft tissue  plasmacytomas is required. |       |             |            |    |
| Minor response (MR)                                                                                                                                                                                                                                                                                   | >25% but <49% reduction of serum M protein and  reduction in 24 h urine M protein by 50–89%, which still  exceeds 200mg per 24 h. In addition to the above criteria,                                                                                                                                                                                                                                                                                                                                                                                                                             |       |             |            |    |
| CASE 4A13 A9 04/03/2017                                                                                                                                                                                                                                                                               | 72                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |       |             |            |    |  
if present at baseline, 25–49% reduction in the size of soft tissue plasmacytomas is also required. No increase in size or number of lytic bone lesions (development of compression fracture does not exclude response).  
Stable disease (SD) Not meeting criteria for sCR, CR, VGPR, PR, MR, or progressive disease (see under 5.9.1).
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8.1.1 progressive disease

Progressive disease (PD) is defined according to the international uniform response criteria
(Durie et al. Leukemia 20:1467-73, 2006, ERRATUM Durie et al. Leukemia 21:1134, 2007) and requires any of the following, confirmed on two consecutive assessments:  
An increase of 25% from lowest response value in **any one or more** of the following:
Serum M-component (absolute increase must be >0.5 g/100 ml) *
Urine M-component (absolute increase must be >200mg per 24 h) Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels (absolute increase must be >100 mg/l)
Bone marrow plasma cell percentage (absolute % must be >10%)
And / or:
Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas Development of hypercalcemia (corrected serum calcium >11.5 mg/100 ml) that can be attributed solely to the plasma cell proliferative disorder
*: If the starting serum m-protein level is >5g/dL an absolute increase of >1g/dL, verified on two consecutive measurements, is sufficient to define progressive disease. The decision as to when to repeat the assessment to document progressive disease will be left at the discretion of the treating physician, there is no need to wait until the next scheduled response assessment.
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9 safety assessments

Safety assessments will consist of monitoring and recording all adverse events and serious adverse events, the regular monitoring of hematology, blood chemistry and urine values, vital signs, ECOG performance status, and the regular physical examinations and ECG assessments. Adverse events will be assessed according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0. CTCAE v4.03 can be accessed on the NIH/NCI website at (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev4.pdf))
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9.1.1 adverse events

Information about all adverse events, whether volunteered by the subject, discovered by investigator questioning, or detected through physical examination, laboratory test or other means, will be collected and recorded and followed as appropriate. An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. Medical conditions/diseases present before starting study drug are only considered adverse events if they worsen after starting study drug. Abnormal laboratory values or test results constitute adverse events only if they induce clinical signs or symptoms, are considered clinically significant, or require therapy.  
The occurrence of adverse events should be sought by non-directive questioning of the patient at each visit during the study. Adverse events also may be detected when they are volunteered by the patient during or between visits or through physical examination, laboratory test, or other assessments. As far as possible, each adverse event should be evaluated to determine: 1. the severity grade (mild, moderate, severe) or (grade 1-4) 2. its relationship to the study drug(s) (suspected/not suspected) 3. its duration (start and end dates or if continuing at final exam) 4. action taken (no action taken; study drug dosage adjusted/temporarily interrupted; study drug permanently discontinued due to this adverse event; concomitant medication taken; non-drug therapy given; hospitalization/prolonged hospitalization)
5. whether it constitutes a serious adverse event (SAE)
All adverse events should be treated appropriately. Such treatment may include changes in study drug treatment including possible interruption or discontinuation, starting or stopping concomitant treatments, changes in the frequency or nature of assessments, hospitalization, or any other medically required intervention. Once an adverse event is detected, it should be followed until its resolution, and assessment should be made at each visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to the study drug, the interventions required to treat it, and the outcome.  
Information about common side effects already known about the investigational drug can be found in the Investigators' Brochures for panobinostat and MLN9708 or will be communicated between IB updates in the form of Investigator Notifications. This information will be included in the patient informed consent and should be discussed with the patient during the study as needed.
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9.1.2 vital signs

Vital sign assessment consists of height (first visit), pulse, blood pressure, respiration rate, temperature and weight. Blood pressure, pulse and respiration rate should be measured on patients after at least 3 minutes in the sitting position
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9.1.3 physical examination

Physical examination will be performed which must comprise a total body examination (general appearance, skin, neck, including thyroid, eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities and basic nervous system).  
CASE 4A13 A9 04/03/2017 74 Significant findings made after the start of study drug which meet the definition of an Adverse Event must be recorded. 9.1.4 **Laboratory evaluations** Laboratory evaluation should be done at baseline (within ≤ 72 hours prior to dosing prior to the first administration of study drugs, during the course of the study and at the time of the study treatment completion visit. Results must be reviewed prior to administering panobinostat (LBH589) and ixazomib (MLN9708). More frequent examinations may be performed if medically indicated; results should be recorded.
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hematology

Hematology must include hemoglobin, hematocrit, platelets, total white blood cell count (WBC) and differential. The coagulation profile includes a prothrombin time or International Normalized Ratio (INR) and activated partial thromboplastin time.
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blood chemistry

Biochemistry includes the following parameters: BUN, creatinine, sodium, potassium, chloride, CO2 (HCO3), glucose, calcium, albumin, total protein, total bilirubin, alkaline phosphatase, AST/SGOT, ALT/SGPT, and magnesium (where indicated in 8). If total bilirubin is greater than the upper limit of normal, direct and indirect bilirubin should be performed.
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thyroid function test

Thyroid Stimulating Hormone (TSH), free T3, and FTI will be measured at baseline, about 3 months after study entry (+/- 14 days), at the study completion, and as deemed clinically necessary during the course of the study.
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9.1.5 serum pregnancy test

All females of childbearing potential should complete a serum pregnancy test within 7 days prior to the administration of study drugs on day 1 of cycle 1. The pregnancy test should be repeated in week 1 of every cycle (except for cycle 1). Postmenopausal women must have been amenorrheic for ≥ 12 months in order to be considered "of non-childbearing potential".
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9.1.6 ecg

See Section 7.1.3 (Cardiac precaution) Section 7.5.4 **(Dose modification for prolonged**
QTc) for guidelines on the required close monitoring of patients' serum biochemistry values
(in particular, potassium and magnesium) and the requirement for rapid correction of low values). A screening 12-lead ECG will be performed to assess study eligibility. Additional 12-lead ECGs will be performed at a minimum at scheduled time points as indicated in Section 8. For all patients, a 12-lead ECGsmust be performed on cycle 1 day 1 prior to the first administration of CASE 4A13 A9 04/03/2017 75 study drugs or within 24 hours prior to that day. This is necessary to get an accurate baseline QTcF calculation.  
Table 9-1 **Cardiac assessment monitoring schedule**  
| Cycle                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Day of cycle                          | ECG monitoring a             |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------|------------------------------|
| Screening b                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Single ECG to assess eligibility      |                              |
| Cycle 1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | 1, 5                                  | Pre-dose: Single 12 lead ECG |
| 1, 5                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | 3 hours post dose: Single 12 lead ECG |                              |
| Cycle 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | 1                                     | Pre-dose: Single 12 lead ECG |
| a Refer to Table 6-7 for the recommended dose modifications due to QTc interval prolongation b The screening ECGs will be analyzed locally to assess eligibility of the patient. (Note: the mean QTc  interval at baseline must be ≤ 470 msec for the patient to be eligible for participation in the trial) Note: If no significant QTcF prolongation is noted during the first 4 cycles, the QTc monitoring is no  longer required and may be performed at the Investigator's discretion, if medically indicated. |                                       |                              |
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9.1.6.1 performance status

Performance status will be assessed according to the ECOG Performance Status Scale:  
| SCORE   | DESCRIPTION                                                                                                                                                  |
|---------|--------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 0       | Fully active, able to carry on all pre-disease performance without  restriction.                                                                             |
| 1       | Restricted in physically strenuous activity but ambulatory and  able to carry out work of a light or sedentary nature, e.g., light  house work, office work. |
| 2       | Ambulatory and capable of all self-care but unable to carry out  any work activities. Up and about more than 50% of waking  hours.                           |
| 3       | Capable of only limited self-care, confined to bed or chair more  than 50% of waking hours.                                                                  |  
CASE 4A13 A9 04/03/2017 76  
| 4                         | Completely disabled.   | Cannot carry on any self-care.   | Totally   |
|---------------------------|------------------------|----------------------------------|-----------|
| confined to bed or chair. |                        |                                  |           |
| 5                         | Dead.                  |                                  |           |
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9.1.6.2 special tests

No special tests will be obtained. Routine standard myeloma tests will be obtained as outlined in Section 8.
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10 safety monitoring 10.1 novartis

To ensure patient safety, every SAE, regardless of suspected causality, occurring after the patient has provided informed consent and until at least 30 days after the patient has stopped study treatment must be reported to Novartis within 24 hours of learning of its occurrence. Any SAEs experienced after this 30 days period should only be reported to Novartis if the investigator suspects a causal relationship to the study treatment. Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-up to the original episode within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a different time interval or otherwise considered completely unrelated to a previously reported one should be reported separately as a new event. Information about all SAEs is collected and recorded on the Serious Adverse Event Report Form as outlined per contractual agreement; all applicable sections of the form must be completed in order to provide a clinically thorough report. The investigator must assess and record the relationship of each SAE to each specific study treatment (if there is more than one study treatment), complete the SAE Report Form in English, and send the completed, signed form by fax within 24 hours to the oncology Novartis Drug Safety and Epidemiology (DS&E) department. The telephone and telefax number of the contact persons in the local department of Drug Safety and Epidemiology (DS&E) are included in the contractual agreement. The original copy of the SAE Report Form and the fax confirmation sheet should be kept with the case report form documentation at the study site. Follow-up information is sent to the same contact(s) to whom the original SAE Report Form was sent, using a new SAE Report Form stating that this is a follow-up to the previously reported SAE and giving the date of the original report. Each re-occurrence, complication, or progression of the original event should be reported as a follow-up to that event regardless of when it occurs. The follow-up information should describe whether the event has resolved or continues, if and how it was treated, whether the blind was broken or not, and whether the patient continued or withdrew from study participation.  
If the SAE is not previously documented in the Investigator's Brochure or Package Insert (new occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis Drug Safety and Epidemiology (DS&E) department associate may urgently require further information from the investigator for Health Authority reporting. Novartis may need to issue an Investigator Notification (IN), to inform all investigators involved in any study with the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and relevant ethics committees in accordance with Directive 2001/20/EC or as per national regulatory requirements in participating countries.
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10.2 millennium instructions for rapid

All serious adverse events (SAEs) (regardless of expectedness or causality) must be reported to Millennium Pharmacovigilance (or designee). See also Novartis Instructions for rapid notification of serious adverse events for the reporting of SAEs. The sponsor-investigator is responsible to meet all regulations and requirements applicable to the sponsor-investigator. Adverse events (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 must be reported to Millennium Pharmacovigilance (or designee). 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 1 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. For serious pretreatment events, the investigator must determine both the intensity of the event and the relationship of the event to study procedures. This is an investigator-initiated study. The principal investigator, Jason Valent (who may also sometimes be referred to as the sponsor-investigator), is conducting the study and acting as the sponsor. Therefore, the legal/ethical obligations of the principal investigator include both those of a sponsor and those of an investigator. Regardless of causality, SAEs and serious pretreatment events (as defined in Section 10.7) must be reported by the sponsor- to the Millennium Pharmacovigilance or designee by faxing the SAE Report using the US FDA MedWatch 3500A Form :
Fatal and Life Threatening SAEs within 24 hours but no later than 4 calendar days 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 The SAE report must include at minimum:
Event term(s)
CASE 4A13 A9 04/03/2017 78
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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 4.0 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.
In the event that this is a multisite study, the sponsor-investigator is responsible to ensure that the SAE reports are sent to Millennium 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 Millennium Pharmacovigilance. Millennium Pharmacovigilance (or designee) may request follow-up information to a reported SAE or serious pretreatment event, which the sponsor-investigator will be responsible for providing to Millennium Pharmacovigilance or designee. Millennium will provide a sample SAE Report Form representative of the information Millennium Pharmacovigilance may request in follow-up. Planned hospital admissions or surgical procedures for an illness or disease that existed before the patient was enrolled in the study are not to be considered AEs unless the condition deteriorated in an unexpected manner during the study (e.g., surgery was performed earlier or later than planned). For both serious and nonserious AEs, the investigator must determine both the intensity of the event and the relationship of the event to study drug administration. For serious pretreatment events, the investigator must determine both the intensity of the event and the relationship of the event to study procedures.  
Intensity for each AE, including any lab abnormality, will be determined by using the NCI
CTCAE, version 4.0 as a guideline, whenever possible. The criteria are available online at http://ctep.cancer.gov/reporting/ctc.html Relationship to study drug administration will be determined by the investigator or subinvestigator 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 Millennium Pharmacovigilance with a copy of all communications with applicable regulatory authorities related to study product(s), as soon as possible but no later than 4 calendar days of such communication.
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sae and pregnancy reporting contact

Millennium Pharmacovigilance or Designee FAX Number 1-800-963-6290 Reporting Form:
US FDA MedWatch 3500A:
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm
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10.3 any other form deemed

Adverse Events of Special Interest (AESIs) are a subset of AEs that are to be reported to Millennium on a quarterly basis by the sponsor-investigator. Millennium will provide the current list of AESIs and updates to the list will be distributed to the sponsor-investigator as appropriate
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10.4 millennium rules for monitoring

AEs will be reported from the first dose of MLN9708 through 30 days after administration of the last dose of MLN9708. In addition, skeletal-related events that occur during the follow-up periods must be reported from the first dose of MLN9708 through death or termination of the study by the sponsor-investigator or Millennium.  
Serious pretreatment events will be reported to Millennium Pharmacovigilance or designee from the time of the signing of the informed consent form (ICF) up to first dose of MLN9708.  
Related and unrelated SAEs will be reported to Millennium Pharmacovigilance or designee from the first dose of MLN9708 through 30 days after administration of the last dose of MLN9708. 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). In addition, new primary malignancies that occur during the treatment or follow-up periods must be reported, regardless of causality to study regime. All new cases of primary malignancy must be reported to Millennium Pharmacovigilance (or designee). Follow up for detection of second primary malignancies beyond the planned study is not required; however, if the sponsorinvestigator learns about the occurrence of a second primary malignancy in one of the study subjects within 3 years after the last study drug administration he must report the event to Millennium Pharmacovigilance (or designee).
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10.5 procedures for reporting drug

Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or disease state) of a female subject occurring while the subject is participating in this study, or within 28 days of the subject's last dose of MLN9708, are considered immediately reportable events. Study drug(s) is to be discontinued immediately. Millennium or designee must also be contacted immediately by faxing a completed Pregnancy Form to the Millennium Department of Pharmacovigilance. The pregnancy must be followed for the final pregnancy outcome. The pregnancy, suspected pregnancy, or positive pregnancy test must be reported to MPI/PPD Drug Safety immediately by facsimile, or other appropriate method, using the Pregnancy Initial Report Form, or approved equivalent form. The female subject should be referred to an obstetrician-gynecologist, preferably one experienced in reproductive toxicity for further evaluation and counseling. The Sponsor-Investigator will follow the female subject until completion of the pregnancy, and must notify MPI/PPD Drug Safety immediately about the outcome of the pregnancy (either normal or abnormal outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form. If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the Sponsor-Investigator should report the abnormal outcome as an AE. If the abnormal outcome meets any of the serious criteria, it must be reported as an SAE to MPI/PPD Drug Safety immediately by facsimile, or other appropriate method, as soon as possible but no later than 5 calendar days of the Sponsor-Investigator's knowledge of the event using the SAE Report Form, or approved equivalent form. All neonatal deaths that occur within 28 days of birth should be reported, without regard to causality, as SAEs. In addition, any infant death after 28 days that the Sponsor-Investigator suspects is related to the in utero exposure to the IP should also be reported to MPI/PPD Drug Safety immediately by facsimile, or other appropriate method, as soon as possible but no later than 5 calendar days of the Sponsor-Investigator's knowledge of the event using the SAE Report Form, or approved equivalent form. Male Subjects If a female partner of a male subject taking investigational product becomes pregnant, the male subject taking study drug must notify the Sponsor-Investigator, and the pregnant female partner should be advised to call their healthcare provider immediately. Millennium or designee must also be contacted immediately by faxing a completed Pregnancy Form to the Millennium Department of Pharmacovigilance. Every effort should be made to follow the pregnancy for the final pregnancy outcome.
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10.6 millennium 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 (see below) and report the event. Whenever possible, the associated product should be maintained in accordance with the label instructions pending further guidance from a Millennium Quality representative.  
For Product Complaints, call MedComm Solutions at 877-674-3784 (877 MPI DRUG)
(US and International)
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 PPD (refer to Section 8.2).
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10.7 serious adverse events

Serious adverse event (SAE) is defined as one of the following: - Is fatal or life-threatening  
- Results in persistent or significant disability/incapacity - Constitutes a congenital anomaly/birth defect - Is medically significant, i.e., defined as an event that jeopardizes the patient or may require medical or surgical intervention to prevent one of the outcomes listed above
- Requires inpatient hospitalization or prolongation of existing hospitalization, - Note that hospitalizations for the following reasons should not be reported as serious adverse events:
- Routine treatment or monitoring of the studied indication, not associated with any deterioration in condition - Elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication under study and has not worsened since signing the informed consent - Social reasons and respite care in the absence of any deterioration in the patient's general conditionNote that treatment on an emergency outpatient basis that does not result in hospital admission and involves an event not fulfilling any of the definitions of a SAE given above is not a serious adverse event
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10.8 pregnancies

To ensure patient safety, each pregnancy occurring while the patient is on study treatment must be reported to Novartis (and Millennium, see under 10.5) within 24 hours of learning of its occurrence. The pregnancy should be followed up to determine outcome, including spontaneous or voluntary termination, details of the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or newborn complications. Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). Pregnancy follow-up should be recorded on the same form and should include an assessment of the possible relationship to the panobinostat any pregnancy outcome. Any SAE experienced during pregnancy must be reported on the SAE Report Form.Pregnancy outcomes must be collected for the female partners of any males who took study treatment in this study. Consent to report information regarding these pregnancy outcomes should be obtained from the mother.
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11 protocol amendments or changes

Any change or addition (excluding administrative) to this protocol requires a written protocol amendment that must be reviewed by Novartis, Millennium, and the sponsor-investigator before implementation. Amendments significantly affecting the safety of subjects, the scope of the investigation or the scientific quality of the study require additional approval by the IRB at each study center. A copy of the written approval of the IRB must be provided to Novartis and Millennium. Examples of amendments requiring such approval are: 1. increases in drug dose or duration of exposure of subjects,  
2. significant changes in the study design (e.g. addition or deletion of a control group), 3. increases in the number of invasive procedures, 4. addition or deletions of a test procedure required for monitoring of safety.
These requirements for approval should in no way prevent any immediate action from being taken by the investigator or by Novartis in the interests of preserving the safety of all patients included in the trial. If an immediate change to the protocol is felt to be necessary by the investigator and is implemented for safety reasons Novartis must be notified and the IRB at the center must be informed immediately. Amendments affecting only administrative aspects of the study do not require formal protocol amendments or IRB approval but the IRB must be kept informed of such administrative changes. Examples of administrative changes not requiring formal protocol amendments and IRB approval include:
1. changes in the staff used to monitor trials  
2. minor changes in the packaging or labeling of study drug.
Any departures from the protocol must be fully documented in the source documents.
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12 data review and management

12.2 Analyses and Reporting Oncore will be used for data entry and analysis. Data will be analyzed and reported in abstract form after the last patient has completed the first cycle and a full manuscript will be submitted once the last patient has gone off this up to 6 month duration study. In addition, interim CASE 4A13 A9 04/03/2017 83 reports may be submitted as abstracts.Data Safety Monitoring PlanThis protocol will adhere to the policies of the Case Comprehensive Cancer Center Data and Safety Monitoring Plan in accordance with NCI regulations.
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12.3 study monitoring

Internal monitoring by quality control teams of the Cleveland Clinic Taussig Cancer Institute and the Seidman Cancer Center of University Hospitals of Case Western University will occur as per Case Comprehensive Cancer Center standard operating procedures for monitoring of investigator initiated trials QA-8.1.0.
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12.3.1 investigator responsibilities

Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice (GCP) and in the US Code of Federal Regulations. Investigators must enter study data onto CRFs or other data collection system. The Investigator will permit study-related audits by Novartis and Millennium or its representatives, IRB/EC review, and regulatory inspection(s) (e.g., FDA, EMEA, TPP), providing direct access to the facilities where the study took place, to source documents, to CRFs, and to all other study documents. The Investigator, or a designated member of the Investigator's staff, must be available at some time during audits to review data and resolve any queries and to allow direct access to the subject's records (e.g., medical records, office charts, hospital charts, and study related charts) for source data verification. The data collection must be completed prior to each visit and be made available to the Novartis and Millennium so that the accuracy and completeness may be checked.
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13 statistical methods 13.1 datasets

This study will use a 3 + 3 design (see under 5) to estimate whether select doses of MLN9708 up to a maximal target dose, chosen based on available data from other studies, are tolerated when combined with fixed doses of panobinostat and dexamethasone. Tolerance will be based on the ratio of patients developing dose limiting toxicity (DLT). Dose increase is allowed if 0 or 3 patients or 1 of 6 patients develop DLTs, while confirmation of a given dose level as tolerated requires treatment of at least 6 patients with no more than one patient developing a DLT. Dose limiting toxicity (DLT) will be assessed during the first cycle and be defined as the following drug-related adverse events according to CTCAE version 4.03 (if an adverse event is attributed to progressive disease, it will not be counted as DLT):  
Grade 4 or higher neutropenia or thrombocytopenia that does not resolve to grade 3 or lower within 7 days after detection while MLN9708 (ixazomib) and panobinostat are held.  
QTcF increase to > 480 msec that persists > 7 days after withholding panobinostat and MLN9708 Any grade 3 or higher non-hematologic adverse events except:
o Nausea, vomiting, diarrhea, or electrolyte abnormalities that can be reduced to grade 2 with supportive measures within 7 days
Patients who cannot be assessed for DLT due to progressive disease or other reasons will be replaced.
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13.1.1.2 safety

Data from all subjects who receive any protocol therapy will be included in the safety analyses. Subjects who entered the study and did not receive any protocol therapy and had this confirmed, will not be evaluated for safety. Adverse events will be recorded during the entire study, weekly during the first cycle, and at the start of each cycle for subsequent cycles. Toxicity will be graded according to CTCAE v.4.0 whenever possible and reported in a descriptive way.
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13.1.2 secondary objectives and endpoints

The response rate (RR= sCR+CR+VGPR+PR) and clinical benefit response rate (CBRR=sCR+CR+VGPR+MR) will be calculated for the entire study group, and for individual dose levels. Since the number of patients treated at any given dose level will be small, any report will mainly list the number of responses but may also mention the percentage of patients achieving a response.
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13.1.2.2 pfs and os

Progression-free survival will be measured from study entry to progression or death of any cause, whichever comes first. Overall survival for all will be measured from study entry to death from any cause. Due to small sample size and limit of treatment duration to six months only observed PFS and OS will be reported for patients participating in phase I. For patients who enter on phase II the Kaplan-Meier method will be used to estimate PFS and OS.
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14 procedures and instructions 14.1

Any formal presentation or publication of data from this trial may be published after review and comment by Novartis and Millennium and prior to any outside submission. Novartis and CASE 4A13 A9 04/03/2017 85 Millennium must receive copies of any intended communication in advance of publication (at least fifteen working days for presentational materials and abstracts and thirty working days for manuscripts). These requirements acknowledge Novartis' and Millennium's responsibility to provide peer input regarding the scientific content and conclusions of such publications or presentations. Principal Investigation/Institution shall have the final authority to determine the scope and content of its publications, provided such authority shall be exercised with reasonable regard for the interests of Novartis and Millennium and, in accord with the trial contract and shall not permit disclosure of Novartis or Millennium confidential or proprietary information.
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14.2 disclosure and confidentiality

The investigator agrees to keep all information provided by Novartis and Millennium in strict confidence and to request similar confidentiality from his/her staff and the IRB/IEC/REB. Study documents provided by Novartis (investigators' brochures and other material) will be stored appropriately to ensure their confidentiality. The information provided by Novartis to the investigator may not be disclosed to others without direct written authorization from Novartis, except to the extent necessary to obtain informed consent from patients who wish to participate in the trial.
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14.3 discontinuation of study

Novartis and Millennium reserve the right to discontinue any study under the conditions specified in the clinical trial agreement.
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15 ethics and good clinical

This study must be carried out in compliance with the protocol and the principles of Good Clinical Practice, as described in Novartis and Millennium standard operating procedures and:  
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. Directive 91/507/EEC, the Rules Governing Medicinal Products in the European Community.  
2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 concerning informed consent and IRB regulations).  
3. Declaration of Helsinki and amendments, concerning medical research in humans
(Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects).
The investigator agrees to adhere to the instructions and procedures described in it and thereby to adhere to the principles of Good Clinical Practice that it conforms to.
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15.1 institutional review board/independent ethics

Before implementing this study, the protocol, the proposed informed consent form and other information to subjects, must be reviewed by a properly constituted Institutional Review Board/Independent Ethics Committee/Research Ethics Board (IRB/IEC/REB). A signed and dated statement that the protocol and informed consent have been approved by the IRB/IEC/REB must be given to Novartis and Millennium before study initiation. Any CASE 4A13 A9 04/03/2017 86 amendments to the protocol, other than administrative ones, must be reviewed by Novartis and Millennium and approved by this committee.
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15.2 informed consent

The investigator must explain to each subject (or legally authorized representative) the nature of the study, its purpose, the procedures involved, the expected duration, the potential risks and benefits involved and any discomfort it may entail. Each subject must be informed that participation in the study is voluntary and that he/she may withdraw from the study at any time and that withdrawal of consent will not affect his/her subsequent medical treatment or relationship with the treating physician. This informed consent should be given by means of a standard written statement, written in non-technical language. The subject should read and consider the statement before signing and dating it, and should be given a copy of the signed document. If the subject cannot read or sign the documents, oral presentation may be made or signature given by the subject's legally appointed representative, if witnessed by a person not involved in the study, mentioning that the patient could not read or sign the documents. No patient can enter the study before his/her informed consent has been obtained. The informed consent form is considered to be part of the protocol, and must be submitted by the investigator with it for IRB/IEC/REB approval.
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15.3 investigator and site responsibility

Accountability for the study drug at all study sites is the responsibility of the principal investigator. The investigator will ensure that the drug is used only in accordance with this protocol. Drug accountability records indicating the drug's delivery date to the site, inventory at the site, use by each patient, and amount returned to Millennium and/or Novartis or a designee or disposal of the drug (if applicable and if approved by Millennium and/or Millennium) will be maintained by the clinical site. Accountability records will include dates, quantities, lot numbers, expiration dates (if applicable), and patient numbers.  
15.4 Record Retention The investigator will maintain all study records according to the ICH-GCP and applicable regulatory and IRB requirement(s).
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16 use of information

All information regarding MLN9708 supplied by Millennium to the investigator is privileged and confidential information. The investigator agrees to use this information to accomplish the study and will not use it for other purposes without consent from Millennium. It is understood that there is an obligation to provide Millennium with complete data obtained during the study. The information obtained from the clinical study will be used toward the development of MLN9708 and may be disclosed to regulatory authority(ies), other investigators, corporate partners, or consultants as required. Upon completion of the clinical study and evaluation of results by Millennium, the hospital or institution and/or investigator may publish or disclose the clinical trial results pursuant to the terms contained in the applicable Clinical Trial Agreement.
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17 references

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14. Siegel DS, Laura McBride L, Bilotti E, et al. Vorinostat Overcomes LenalidomideDexamethasone and Lenalidomide-Bortezomib-Dexamethasone Resistance In Relapsed/Refractory Multiple Myeloma. *Blood (ASH Annual Meeting Abstracts) 116:*
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15. Christian B, Kopko A, Fehniger TA, Bartlett NL, Kristie A. Blum KA. A Phase I Trial of the Histone Deacetylase (HDAC) Inhibitor, Panobinostat, in Combination with Lenalidomide in Patients with Relapsed/Refractory Hodgkin's Lymphoma (HL). Blood (ASH Annual Meeting Abstracts). 2012;120: Abstract 1644.  
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44. Fuino L, Bali P, Wittmann S, et al. Histone deacetylase inhibitor LAQ824 downregulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B. *Mol Cancer Ther.* Oct 2003;2(10):971-984.  
45. Nimmanapalli R, Fuino L, Bali P, et al. Histone deacetylase inhibitor LAQ824 both lowers expression and promotes proteasomal degradation of Bcr-Abl and induces apoptosis of imatinib mesylate-sensitive or -refractory chronic myelogenous leukemiablast crisis cells. *Cancer Res.* Aug 15 2003;63(16):5126-5135.  
46. Yu X, Guo ZS, Marcu MG, et al. Modulation of p53, ErbB1, ErbB2, and Raf-1 expression in lung cancer cells by depsipeptide FR901228. *J Natl Cancer Inst.* Apr 3 2002;94(7):504-513.  
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18 appendices

19 Medications which have a risk of causing Torsades de pointes ventricular arrhythmia should be avoided Patients who are currently receiving treatment of the medications in Table 19-1 and cannot either discontinue from this treatment or switch to an alternative medication prior to enrollment in a panobinostat clinical study, will be excluded from the study. Patients may not begin panobinostat treatment with any of the medications listed in Table unless this is discussed with the Sponsor and an approval is granted by the Sponsor. The sponsor may agree to temporarily discontinue panobinostat treatment (e.g., for 72 hours) during administration with these drugs or withheld medications in Table 19-1 for at least 72 hours when panobinostat is to be administered. NOTE: It is of great importance to avoid combining drugs listed below in Table 19-1 and Table 20-1 (CYP3A inhibitors) especially in the presence of electrolyte abnormalities, notably decreased potassium or magnesium levels commonly associated with diuretic usage. In generally, medications listed in Table 19-1 should be avoided while medications listed in Tables 20-1 and Table 21-1 are to be used with caution when co-administered with panobinostat. Please select the most stringent recommendation for concomitant medications (i.e., to be avoided) which are common among the tables (e.g., erythromycin, clarithromycin)
Table 19-1 **Medications which have a risk of causing Torsades de pointes to be avoided**
All **Class IA antiarrhythmics**  
|                                                                                                                                                                                                                                                 | quinidine                              |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------|
|                                                                                                                                                                                                                                                 | procainamide                           |
|                                                                                                                                                                                                                                                 | disopyramide                           |
|                                                                                                                                                                                                                                                 | any other class IA antiarrhythmic drug |
| All Class III antiarrhythmics  amiodarone sotalol bretylium disopryramide dofetilide ibutilide any other class III antiarrhythmic drug Antibiotics Macrolide antibiotics*  erythromycin  clarithromycin  telithromycin Quinolone antibiotics* |                                        |  
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*Note: azithromycin, levofloxacin, pefloxacin, ofloxacin, tosufloxacin, difloxacin, temafloxacin, fleroxacin, acrosoxacin, and nalidixic acid are allowed.  
This is not a comprehensive list of medications which may prolong the QT interval or have a risk of causing Torsades de pointes. This list of medications was developed in collaboration with an external cardiology consultant, and represents those medications which are deemed to have an unacceptable risk of co-administration with panobinostat.  
The following website may be referenced as a supplemental guide for drugs which have been associated with Torsades de pointes or prolonging the QT interval but at this point lack substantial evidence for causing Torsades de pointes: http://www.qtdrugs.org/medical-pros/drug-lists/drug-lists.htm\#. Medications listed on the website which do not appear in Table 19-1 above may be used with caution at the discretion of the investigators.  
The serotonin (5HT3) antagonists, often used as antiemetics, such as ondansetron dolasetron,
(also are known CYP2D6 substrates, see Table 21-1), or granisetron have been associated with Torsades de points and QT prolongation but have not been shown to cause Torsades de pointes.  
Therefore, 5HT3 antagonists are not per se prohibited but close monitoring for signs and symptoms of QT prolongation is recommended. Caution is to be exercised when using these or other agents that may prolong QT intervals in combination with panobinostat.
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20 medications which are known

Panobinostat is a substrate of CYP3A4 with minor involvement of CYP2D6, and CYP2C19 in in vitro evaluation of its metabolism. Thus, a clinical drug-drug interaction study was conducted using ketoconazole, a strong CYP3A inhibitor, in combination with panobinostat in study CLBH589B2110.  
Multiple ketoconazole doses at 400 mg increased Cmax and AUC of panobinostat by 1.6- and 1.8-fold, respectively, but with no change in Tmax or half-lives in 14 cancer patients. The less than 2-fold increase in panobinostat AUC upon co-administration of a strong CYP3A inhibitor is considered a weak drug inhibition and not clinically relevant, as panobinostat doses at least 2-fold greater than the evaluated 20 mg dose (i.e., 40 mg and 60 mg) have been safely administered in patients. Thus, co-administration of panobinostat with a moderate or weak CYP3A inhibitor is allowed. However, clinical monitoring of signs and symptoms of panobinostat treatment related adverse events is recommended when long-term (≥ 1 week) concomitant administration of any strong CYP3A inhibitors and panobinostat is medically indicated or investigated in a clinical study.  
Patients with impaired liver function (as defined by NCI CTEP criteria)1 are recommended not to receive panobinostat concomitantly with strong CYP3A inhibitors because potential interaction has not been established in this population.  
Table 20-1 **Medications which are known strong CYP3A4/5 inhibitors to be used with**
caution  
  
  
  
 Antidepressants  
  
**saquinavir**
Miscellaneous drugs or products
**aprepitant**
grapefruit product or juice
* azithromycin, regular orange juice and dihydropyridine calcium channel blockers (e.g. amlodipine, felodipine, nicardipine, nifedipine) are allowed.  
This is not a comprehensive list of medications which may inhibit CYP3A4/5. Additional updated versions with moderate and weak CYP3A inhibitors, which are meant to be used as a guide, may be found at the following website: http://medicine.iupui.edu/clinpharm/DDIs
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21 medications which are known

Panobinostat was also shown to be a CYP2D6 inhibitor (Ki 0.17 µM) *in vitro*. Thus, clinical drug-drug interaction study with panobinostat as CYP2D6 inhibitor and dextromethorpan as CYP2D6 substrate was recently conducted in study CLBH589B2109. Multiple panobinostat doses increased Cmax and AUC of dextromethorphan by a mean of 1.8and 1.6-fold respectively, but with no change in Tmax in 17 cancer patients. An approximately 2-fold increase in dextromethorphan AUC upon co-administration with panobinostat indicated that *in vivo* CYP2D6 inhibition of panobinostat is weak. As the study was conducted using a sensitive CYP2D6 substrate which resulted in a weak inhibition, drugs with a large therapeutic index such as anti-emetics, anti-hypertensives, and anti-depressants are generally safe to be co-administered with panobinostat. Patients should be carefully monitored for potential signs and symptoms of toxicity and may require dose titration or dose reduction of a sensitive CYP2D6 substrate which also have a narrow therapeutic window (e.g., the ratio of toxicity exposure is ≤ 2-fold higher than the efficacious or therapeutic exposure).  
| Beta blockers (listed below):   | Antipsychotics (listed below):   |
|---------------------------------|----------------------------------|
| carvedilol                      | aripiprazole                     |
| metoprolol                      | haloperidol                      |
| propafenone                     | perphenazine                     |
| timolol                         | risperidone                      |
| Antidepressants (listed below): | thioridazine                     |
| amitriptyline                   | zuclopenthixol                   |
| chlormipramine                  | amphetamine                      |  
Table 21-1 **Medications which are known CYP2D6 substrates to be used with caution**
CASE 4A13 A9 04/03/2017 96  
| Confidential                |                                                                 |
|-----------------------------|-----------------------------------------------------------------|
| desipramine                 | alprenolol                                                      |
| imipramine                  | bufuralol                                                       |
| fluoxetine                  | chloropheniramine                                               |
| paroxetine                  | Antiarrhythmics (listed below):                                 |
| venlafaxine                 | quinidine                                                       |
| bupropion                   | lidocaine                                                       |
| duloxetine                  | mexiletine                                                      |
| Antiemetics (listed below): | propafenone                                                     |
| dolasetron                  | Others:                                                         |
| ondansetron                 | oxycodone                                                       |
| metoclopramide              | codeine hydrocodone terbinafine promethazine tamoxifen tramadol |  
This is not a comprehensive list of CYP2D6 substrates. Additional updated versions of this list, which are meant to be used as a guide, may be found at the following website: http://medicine.iupui.edu/clinpharm/DDIs Synold TW, Takimoto CH, Doroshow JH, Gandara D, Mani S, Remick SC, Mulkerin DL, Hamilton A, Sharma S, Ramanathan RK, Lenz HJ, Graham M, Longmate J, Kaufman BM, Ivy SP. Dose-Escalating and Pharmacological Study of Oxaliplatin in Adult Cancer Patients with Impaired Hepatic Function: A National Cancer Institute Organ Dysfunction Working Group Study, Clin Cancer Res. 2007 *13;* 3660
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22 cockroft-gault estimation of crcl

Cockcroft-Gault estimation of creatinine clearance (CrCl): (Cockcroft, 1976; Luke 1990)  
$\underline{\text{ght},\text{kg})}$
CrCl (mL/min) = (140 –age) x (weight, kg)__
(**Males**) 72 x (serum creatinine, mg/dL)  
$$\mathrm{CrCl}\;(\mathrm{mL/min})=$$
$$(140\,\mathrm{-age})\geq(\mathrm{weight,\,kg})\quad\ge0.85$$  
$$(\mathrm{Females})$$  
  
$$72{\mathrm{~x~(serum~creatinine,~mg/dL)}}$$  
nium Pregnancy Reporting Form Pregnancy Form  v03Nov2008 (IIS)  
2008 (IIS). [Page 1 of 4]
Report Type:      Initial
❏ Follow-up Date of Report:
,
g S
MM
REPORTER INFORMATION: (Please forward if an alternative physician is more appropriate)
Reporter name:
Title:  
| Address:                                                                                                            | Telephone No.:   | Fax No.   |       |
|---------------------------------------------------------------------------------------------------------------------|------------------|-----------|-------|
| City, State/Province:                                                                                               | Postal Code:     | Country:  |       |
| FATHER'S INFORMATION                                                                                                | ❏ Father Unknown |           |       |
| Initials:                                                                                                           | Date of Birth:   | or  Age:  | years |
| D                                                                                                                   | Yr               |           |       |
| Participating in an MPI clinical study?  ❏ No                                                                       | D Yes            |           |       |
| If no, what company product was taken:                                                                              |                  |           |       |
| If yes, please provide:  Study drug:                                                                                | Protocol No:     |           |       |
| Center No:                                                                                                          | Patient No:      |           |       |
| Medical / Familial / Social History                                                                                 |                  |           |       |
| (i.e. Include chronic illnesses: specify, familial birth defects/genetic/chromosomal disorders; habitual exposure:  |                  |           |       |
| specify, alcohol/tobacco; drug exposure: specify, substance abuse and medication use. Please include drug treatment | Race:            |           |       |
| prior to or around the time of conception and/or during pregnancy)                                                  | Occupation:      |           |       |
| Number of children:                                                                                                 |                  |           |       |
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pregnancy form v03nov2008 (iis) page

| MOTHER'S INFORMATION:                                                    |                                         |                               |       |
|--------------------------------------------------------------------------|-----------------------------------------|-------------------------------|-------|
| Initials:                                                                | Date of Birth:                          | or Age:                       | years |
| DO                                                                       | M                                       |                               |       |
| Participating in an MPI clinical study?  ❏ No                            | □ Yes                                   | Race:                         |       |
| If no, what company product was taken:                                   | Occupation:                             |                               |       |
| If yes, please provide:  Study drug:                                     | Protocol No:                            |                               |       |
| Center No:                                                               | Patient No:                             |                               |       |
| Number of previous pregnancies: Full term __                             | Pre-term                                |                               |       |
| Medical / Familial / Social History                                      | Outcomes of previous pregnancies:       |                               |       |
| (i.e. Include alcohol/tobacco and substance abuse; complications of past |                                         |                               |       |
| pregnancy, labor/delivery, fetus/baby; illnesses during this pregnancy;  | (Please indicate number of occurrences) |                               |       |
| assisted conception: specify, other disorders including familia          |                                         |                               |       |
| defects/genetic/chromosomal disorders; method of diagnos                 | - Spontaneous abortion:                 | - Normal live birth:          |       |
| cnsanguinity, etc.)                                                      | - Therapeutic abortion:                 | - Children born with defects: |       |
| - Elective abortion:_                                                    | - Stillbirth:                           |                               |       |
| - Other:                                                                 | - Outcome unknown:                      |                               |       |
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mother's drug exposure information

| Please include medical prescriptions, vaccinations, medical devices, OTC products, pregnancy supplements (such as   |                 |               |             |    |    |    |     |     |
|---------------------------------------------------------------------------------------------------------------------|-----------------|---------------|-------------|----|----|----|-----|-----|
| folic acid, multivitamins)                                                                                          | Route           | Date of first | Date of end |    |    |    |     |     |
| Product                                                                                                             | Contraindicated |               |             |    |    |    |     |     |
| Dosage                                                                                                              | administered    | treatment     | Indication  |    |    |    |     |     |
| Name                                                                                                                | use             | to pregnancy  |             |    |    |    |     |     |
| (DD/MM/Yr)                                                                                                          | (DD/MM/Yr)      |               |             |    |    |    |     |     |
| to patient                                                                                                          | Yes  No  Unk    |               |             |    |    |    |     |     |
| )                                                                                                                   |                 |               |             |    |    |    |     |     |
| (                                                                                                                   | /               | /             | )           | 1. | /  | )  | Yes |     |
| Yes                                                                                                                 |                 |               |             |    |    |    |     |     |
| (                                                                                                                   | /               | /             | )           | /  | )  |    |     |     |
| (                                                                                                                   | /               | /             | )           | (  | /  | /  | )   | Yes |
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pregnancy form v03nov2008 (iis)

.  
Page 3 of 4 CURRENT PREGNANCY INFORMATION  
| Period at exposure:                                                          | weeks                                                  | Trimester   | (2)   | (3)   | Fetal/Neonatal Status   |
|------------------------------------------------------------------------------|--------------------------------------------------------|-------------|-------|-------|-------------------------|
| Date of last menstrual period:                                               | ❏ Normal                                               |             |       |       |                         |
| Pregnancy Status                                                             | ❏ Birth defect (structural/chromosomal disorder)*      |             |       |       |                         |
| ❏ Pregnancy Ongoing                                                          | ❏ Other (non-structural, premature birth, intrauterine |             |       |       |                         |
| Estimated date of delivery:                                                  | death/stillbirth)*                                     |             |       |       |                         |
| ❏ Live Birth                                                                 | D                                                      | MM          | Y     |       |                         |
| □ Stillbirth                                                                 | *If box is checked, please note details in "Additional |             |       |       |                         |
| ❏ Early Termination                                                          | details" section below                                 |             |       |       |                         |
| ❏ Spontaneous abortion*                                                      |                                                        |             |       |       |                         |
| ❏ Therapeutic abortion*                                                      |                                                        |             |       |       |                         |
| ❏ Elective abortion*                                                         |                                                        |             |       |       |                         |
| ❏ Other*:                                                                    |                                                        |             |       |       |                         |
| *If box is checked, please note reason in "Additional Details" section below |                                                        |             |       |       |                         |
| Additional Details:                                                          |                                                        |             |       |       |                         |  
Is there evidence of a defect from a prenatal test?  
■No If yes, indicate which test(s) showed evidence of birth defect:
- Amniocentesis ❏ Chorionic Villi Sampling
❏ Other:
Please specify details of defect(s), disorder(s), and/or other anomaly(ies):
What are the defect(s) attributed to:
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infant information

Pregnancy Form  V03Nov2008 (Iis)  
$\text{Page}4\text{of}4$ .  
| Sex: ❏ Male ❏ Female ❏ Unk                        |                                       |         |                               |       |
|---------------------------------------------------|---------------------------------------|---------|-------------------------------|-------|
| Gestational weeks at birth or at termination:     | _weeks                                | Length: | ❏ cm ❏ in                     |       |
| Date of birth or termination:                     | D                                     | Weight: | O g                           | ❏ Ibs |
| If multiple births (e.g. twins), indicate number: | Head circumference:                   | ❏ cm    |                               |       |
| (Please complete separate form for each child)    | Apgar score (0-10) at 1 minute:       | D Unk   |                               |       |
| Birth Order (1, 2, 3, etc.)  __                   | Apgar score (0-10) at 5 minute:       | ❏ Unk   |                               |       |
| Breast-fed:                                       | ●Yes                                  | ❏ Unk   | Resuscitation required:   Yes |       |
| Method of delivery:                               | Admission to intensive care required: |         |                               |       |
| ❏ Other:                                          | ❏ Yes ❏ No  ❏ Unk                     |         |                               |       |  
Additional Notes:
Please attach RELEVANT LABORATORY TESTS AND PROCEDURES (e.g. results of ultrasounds, amniocentesis, chononic villi sampling, or miscellaneous testing as applicable). In the case of an abnormal evolution or outcome, please send copies of results of all relevant laboratory testing and procedures, including pathology results of products of conception and or autopsy reports if applicable.  
Please submit any additional relevant information on a separate sheet.  
Investigator signature:
Date:
Investigator Name:
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summary of changes april 24

Cover page: added Dr. Campagnaro as UH investigator Section 7.6.1: pg. 61 changed CRF to Oncore Section 8: pg. 69 -70 changes on the schedule of assessments and foot notes for some additional clarifications Pgs. 76-87 administrative changes brought to our attention
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may 6 2014 amendment 2

Table 7.5 pg. 57 the parameters for QTCF was changed to >=481 since it would otherwise contradict parameters to start a new cycle (7.4; QTCF <=480 = grade 1).  
Table 8.1 pg. 69 myeloma parameters removed from day 1 cycle one in schedule of assessments (table 8.1) since they are already included in screening (day -7 to 1) and do not need to be repeated for any safety concerns
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june 18 2014 amendment 3

Section 10.4 pg. 82 Added: Follow up for detection of second primary malignancies beyond the planned study is not required; however, if the sponsor-investigator learns about the occurrence of a second primary malignancy in one of the study subjects within 3 years after the last study drug administration he must report the event to Millennium Pharmacovigilance (or designee).
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december 26 2014 amendment 4

Cover: Replaced Dr. Campagnaro with Dr. William as UH PI  
1. **5.4: Dose Limiting Toxicities: Pg. 42**
Use of G-CSF or platelet transfusions in cycle one Neutropenic fever (with grade 3 or grade 4 neutropenia)
2. **6.1.2: Inclusion/Exclusion: Pg. 45 and 46**
Updated Inclusion Criteria \# 12 added Inclusion criteria \# 13 Updated Exclusion Criteria \# 1 Added \# 2 Updated \#'s 5, 6 and 9 deleted Exclusion criteria \# 11 (was added to Inclusion)
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3. 7.1.3 cardiac precautions -

CASE 4A13 A9 04/03/2017 102 deleted phosphorus 4. **7.4: Instructions for Initiation of a New Cycle: Pg. 52**
Platelets ≥ 50x 109/L, without platelet transfusion for > 72h
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5. 7.5.4 dose modifications for

Dosing delay of > 21 days (= unable to receive study therapy for 22 days including any therapy held during a cycle)
Delay of a cycle by > 14 days from the intended day of the next scheduled dose, counted from the start of the previous cycle.
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7. 7.7.2 summary of prohibited

Non-steroidal anti-inflammatory agents (NSAIDs) should be avoided if possible due to risk for kidney dysfunction in myeloma but if clinical judgement strongly argues for their use patients can remain on study while receiving NSAIDs Platelet transfusions can be given as clinically indicated but eligibility for starting a new cycle needs to be determined after at least 72 h without platelet transfusion and eligibility for inclusion in this trial needs to be determined after at least 7 days without platelet transfusion.
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8. 8.0 visit schedule and

9. **9.1.6: ECG Assessments: Pg. 79**
Updated tables for ECG from 3 to 1
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june 3 2015 amendment 5

**Cover:** Replaced Dr. William with Dr. Malek as UH PI  
**Pg. 3 Dose Levels:** Patient may continue on Panobinostat behind cycle 6 if disease is at least stable disease free of charge.
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pg. 39 section 5.2 study

If the patient's myeloma is controlled in at least stable disease panobinostat may be continued free of charge to the patient. Follow up after completion of cycle 6 is at the discretion of the treating physician but if panobinostat is continued, monitoring for electrolyte abnormalities, especially potassium and magnesium, at a frequency appropriate for the respective patient, is recommended.  
This protocol may be amended to include a formal maintenance phase and/or a phase II portion after review of safety and preliminary efficacy data.
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september 23 2015 amendment 6

Page 1 Increase \# of patients to an additional 20 in the Phase 2 Section 2 Page 40 Rationale for Phase 2 Section 6 Page 44 Study Population Section 6.1.2 Page 44-46 Inclusion Criteria items 3, 8 and 13 Section 6.1.2 Page 48 Exclusion Criteria item 21 Section 8 Page 74-75 Visit schedule and assessments
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july 18 2016 amendment 7

**Pg. 43 Inclusion Criteria \#13 (Added Dara and Elot)** 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.
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pg. 50 section 7.4 instructions

**Deleted:** total serum calcium [corrected for serum albumin] or ionized calcium ≥LLN
**Clarified:** QTcF < 480 msec if ECG obtained (mandatory before cycle 2)
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march 1 2017 amendment 8

Cover Page: Adding NCT \#  
Footer: Updated Addendum: Summary of Changes
April 3, 2017 Cover Page: PI from Dr. Reu to Dr. Valent Footer Updated