Study of the Combination of Panobinostat and Carfilzomib in Patients With Relapsed/Refractory Multiple Myeloma

• Sponsor: SCRI Development Innovations, LLC (Other)
• Overall Status: Completed
• CT.gov ID: NCT01496118
• Collaborator: Onyx Therapeutics, Inc. (Industry), Novartis (Industry)
• Enrollment: 80
• Locations: 13
• Arm: 1
• Duration (Months): 108
• Patients Per Site: 6.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Relapsed/refractory Multiple Myeloma (MM) is an incurable disorder with a poor prognosis. Carfilzomib is a novel proteasome inhibitor with activity in this setting. Panobinostat is a pan-deacetylase inhibitor which has shown synergistic cytotoxicity in vitro and in vivo with proteasome inhibitors. The combination should enhance the activity of both agents against myeloma cells. In Phase I, the optimal doses of the combination of carfilzomib and panobinostat will be determined. Assuming this combination is feasible, the Phase II portion will proceed using the doses determined in Phase I.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: panobinostat; Drug: carfilzomib	Phase 1/Phase 2

Detailed Description

In this open-label, non-randomized Phase I/II study, a maximum of 4 planned dose levels of carfilzomib and panobinostat were evaluated to determine the maximum tolerated dose (MTD) to administer. The MTD was not reached so patients in Phase II received treatment at dose level 4 to further assess efficacy. Response to treatment was evaluated after each 4-week cycle. Those having an objective response or stable disease are continuing treatment until disease progression or unacceptable toxicity occurs.

As the MTD in the 4 planned dose levels were not reached, a parallel Phase I study was initiated to examine additional dose levels using a traditional 3+3 design. If these dose levels are tolerable, then more patients will be recruited into an expansion cohort to assess efficacy at the new dose level(s).

Study Design

• Study Type: Interventional
• Actual Enrollment: 80 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Study of the Combination of Panobinostat and Carfilzomib in Patients With Relapsed/Refractory Multiple Myeloma
• Study Start Date: Dec 1, 2011
• Actual Primary Completion Date: Dec 1, 2020
• Actual Study Completion Date: Dec 1, 2020

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Carfilzomib and Panobinostat Phase I: Carfilzomib: cycle 1 - Dose is 20 mg/m^2 IV on day 1; 27 or 36 or 45 or 56 mg/m^2 IV on Days 8, 9, 15, 16 cycle 2 to progression - 27 or 36 or 45 or 56 mg/m^2 IV on days 1, 2, 8, 9, 15, 16 Panobinostat: cycle 1 and cycle 2 to progression - 20 mg or 30 mg on days 1, 3, 5, 15, 17, 19 Phase II: Carfilzomib and Panobinostat: Dose is optimal dose determined in Phase I

Drug: panobinostat; Specified dose on specified days; Other Names: LBH589 (Panobinostat) ; Drug: carfilzomib; Specified dose on specified days; Other Names: PX-171-007

Outcome Measures

Primary Outcome Measures

1. Number of Phase I Patients (Dose Level 1-6) Experiencing a Dose-Limiting Toxicity (DLT) to Determine the Optimal Dosage [28 days from the start of study treatment]

   Using a traditional 3+3 dose escalation design, successive cohorts of subjects will receive a fixed dose level of the drug combination. The MTD is defined as the highest dose level at which ≤1 of 6 subjects experiences a dose-limiting toxicity (DLT) assessed by NCI CTCAE v4.0. DLT is defined as any of the following that are determined to be related to study treatment during Cycle 1: Grade 4 neutropenia for >7 days, Febrile neutropenia, Grade 3 thrombocytopenia with ≥ Grade 2 bleeding, Grade 4 thrombocytopenia > 7 days, ≥ Grade 2 neuropathy with uncontrolled pain, ≥ Grade 3 non-hematologic drug-related toxicity (excluding alopecia), despite optimal supportive care lasting >72 hours or requiring a dose reduction in the first cycle and Patients who are unable to receive 75% of the required doses of both agents secondary to toxicity. Number of Participants With such Dose Limiting Toxicities (DLT) at each level are reported here.

2. Phase II: Overall Response Rate [up to 6 years]

   Defined as the percentage of patients with confirmed complete response, very good partial response, or partial response (CR, VGPR, or PR) according to International Myeloma Working Group Uniform Response Criteria. CR=bone marrow contains ≤5% plasma cells; negative fixation on serum and urine; disappearance of soft tissue plasmacytomas. VGPR=≥90% reduction from baseline serum; urine M-protein level 100mg for 24h. PR=≥50% reduction from baseline in serum M-protein; disappearance of any soft tissue plasmacytomas.

Secondary Outcome Measures

1. Time-to-progression (TTP) [up to 6 years]

   Measured from date of first treatment until date of first documented progression as per International Myeloma Working Group Uniform Response Criteria. Progressive disease id defined as an increase of ≥ 25% from the nadir in at least one of the following criteria: serum M-protein (absolute increase must be ≥0.5 g/dL); urine M-protein (absolute increase must be ≥200 mg/24h) ; only in patients with non-measurable serum and urine M-protein levels: difference in involved and uninvolved FLC levels (absolute increase must be >10 mg/dL); only in patients with non-measurable serum and urine M-protein levels and non-measurable disease by FLC levels, bone marrow plasma cell percentage (absolute % must be ≥10%) 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 OR Development of hypercalcemia (corrected serum Ca >11.5mg/dL) for patients without hypercalcemia at baseline

2. Progression-free-survival (PFS) [up to 6 years]

   Measured from date of first protocol treatment until date of tumor progression or death as per International Myeloma Working Group Uniform Response Criteria. Progressive disease id defined as an increase of ≥ 25% from the nadir in at least one of the following criteria: serum M-protein (absolute increase must be ≥0.5 g/dL); urine M-protein (absolute increase must be ≥200 mg/24h) ; only in patients with non-measurable serum and urine M-protein levels: difference in involved and uninvolved FLC levels (absolute increase must be >10 mg/dL); only in patients with non-measurable serum and urine M-protein levels and non-measurable disease by FLC levels, bone marrow plasma cell percentage (absolute % must be ≥10%) 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 OR Development of hypercalcemia (corrected serum Ca >11.5mg/dL) for patients without hypercalcemia at baseline

3. Overall-survival (OS) [up to 6 years]

   Measured from time of first study treatment until date of death or date last known alive.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Eligible participants must have multiple myeloma using standard criteria.

2. Patients must have measurable disease requiring systemic therapy defined as at least one of the following:

• Serum M-protein ≥1 g/dl (≥10 g/l)

• Urine M-protein ≥200 mg/24 hrs

• Serum free light chain assay: involved free light chain level ≥10 mg/dl (≥100 mg/l) provided the serum free light chain ratio is abnormal

1. Must have progressed during or after at least one previous bortezomib-containing treatment regimen. Patients who have received previous high-dose therapy/autologous stem cell transplantation are eligible.

2. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

3. Must meet the following laboratory criteria:

• Absolute neutrophil count (ANC) ≥1000/μL;

• Platelets ≥70,000/microL;

• AST or ALT and alkaline phosphatase (ALP) must be ≤ 2.5 x ULN, or ≤ 5 x ULN in patients with plasmacytomas of the liver;

• Total bilirubin ≤ 1.5 x the institutional ULN;

• Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 50 ml/min;

• Serum potassium, calcium, magnesium WNL (These may be corrected prior to starting therapy, to make the patient eligible.)

1. Ability to swallow oral medications.

2. Baseline MUGA or ECHO must demonstrate left ventricular ejection fraction (LVEF) ≥ the lower limit of the institutional limits of normal.

3. Male or females ≥ 18 years of age.

4. Female patients must not be of child-bearing potential or must agree to use adequate contraceptive measures.

5. Male patients willing to use adequate contraceptive measures.

6. Willingness and ability to comply with the trial and follow-up procedures.

7. Ability to understand the nature of this trial and give written informed consent.

Exclusion Criteria:

1. Currently receiving or have received systemic cancer therapy (chemotherapy, biologic therapy) ≤ 21 days of initiating study therapy. For patients receiving small molecule targeted therapy, study treatment may begin >21 days after last dose or >5 half lives of previous treatment, whichever is shorter. Patients must have completed radiation therapy ≥7 days prior to starting study treatment. Patients must have recovered from or come to a new chronic stable baseline from all treatment-related toxicities. Dexamethasone or other high-dose steroid therapy must be stopped ≥ days prior to starting study treatment.

2. Previous treatment with HDAC, DAC, HSP90 or valproic acid for treatment of cancer.

3. Requires valproic acid for any medical condition during the study ≤5 days prior to first panobinostat treatment.

4. Patient has not recovered from all therapy-related toxicities associated with prior treatments to < Grade 2 CTCAE.

5. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib).

6. Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis ≤14 days prior to study entry.

7. Patients using medications that have a risk of prolonging the QT interval or inducing Torsade de Pointes if treatment cannot be discontinued or switched to a different medication prior to receiving study drug.

8. Patients with > grade 2 diarrhea.

9. Patients with impaired cardiac function.

10. Infection requiring IV antibiotics.

11. Patients with > grade 2 peripheral neuropathy or with uncontrolled pain.

12. Women who are pregnant or lactating.

13. Any concurrent medical illness that may impair the ability of the patient to tolerate study treatment and comply with the requirements of the study.

14. Mental condition that would prevent patient comprehension of the nature of, and risk associated with, the study.

15. Use of any non-approved or investigational agent ≤30 days prior to administration of the first dose of study drug. Patients may not receive any other investigational or anti-cancer treatments while participating in this study.

16. Presence of other active cancers, or history of treatment for invasive cancer ≤ 5 years. Patients with stage I cancer who have received definitive local treatment at least 3 years previously, and are considered unlikely to recur are eligible. All patients with previously treated in situ carcinoma (i.e. non-invasive) are eligible, as are patients with history of non-melanoma skin cancer.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Colorado Blood Cancer Institute	Denver	Colorado	United States	80218
2	Florida Cancer Specialists South	Fort Myers	Florida	United States	33916
3	Woodlands Medical Specialists	Pensacola	Florida	United States	32503
4	Florida Cancer Specialists North	Saint Petersburg	Florida	United States	33705
5	Providence Medical Group	Terre Haute	Indiana	United States	47802
6	RHHP/Hope Cancer Center	Terre Haute	Indiana	United States	47802
7	Research Medical Center	Kansas City	Missouri	United States	64132
8	Hematology-Oncology Associates - Northern NJ	Morristown	New Jersey	United States	07962
9	Oncology Hematology Care, Inc.	Cincinnati	Ohio	United States	45242
10	Cancer Centers of Southwest Oklahoma	Lawton	Oklahoma	United States	73505
11	Tennessee Oncology-Chattanooga	Chattanooga	Tennessee	United States	37404
12	Tennessee Oncology	Nashville	Tennessee	United States	37205
13	The Center for Cancer and Blood Disorders	Fort Worth	Texas	United States	76104

Sponsors and Collaborators

• SCRI Development Innovations, LLC
• Onyx Therapeutics, Inc.
• Novartis

Investigators

• Study Chair: Jesus Berdeja, MD, SCRI Development Innovations, LLC

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 3, 2015

More Information

Publications

None provided.

• Responsible Party: SCRI Development Innovations, LLC
• ClinicalTrials.gov Identifier: NCT01496118
• Other Study ID Numbers: SCRI MM 27
• First Posted: Dec 21, 2011
• Last Update Posted: Feb 2, 2022
• Last Verified: Jan 1, 2022

• Keywords provided by SCRI Development Innovations, LLC: Relapsed/Refractory Multiple Myeloma; carfilzomib; panobinostat
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Panobinostat

Study Results

Participant Flow

Arm/Group Title	Dose Level 1	Dose Level 2	Dose Level 3	Dose Level 4	Dose Level 5	Dose Level 6	Expansion Dose Level 4	Expansion Dose Level 6
Arm/Group Description	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 27 mg/m^2 IV D 8, 9, 15, 16; cycle 2 to progression - 27 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 20 mg by mouth D 1, 3, 5, 15, 17, 19 panobinostat: Specified dose on specified days carfilzomib: Specified dose on specified days	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 36 mg/m^2 IV D 8, 9, 15, 16; cycle 2 to progression - 36 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 20 mg by mouth D 1, 3, 5, 15, 17, 19 panobinostat: Specified dose on specified days carfilzomib: Specified dose on specified days	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 45 mg/m^2 IV D 8, 9, 15, 16; cycle 2 to progression - 45 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 20 mg by mouth D 1, 3, 5, 15, 17, 19 panobinostat: Specified dose on specified days carfilzomib: Specified dose on specified days	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 45 mg/m^2 IV D 8, 9, 15, 16; cycle 2 to progression - 45 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 30 mg by mouth D 1, 3, 5, 15, 17, 19 panobinostat: Specified dose on specified days carfilzomib: Specified dose on specified days	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 56 mg/m^2 IV D 8, 9, 15, 16; cycle 2 to progression - 56 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 30 mg by mouth D 1, 3, 5, 15, 17, 19	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 56 mg/m^2 IV D 8, 9, 15, 16; cycle 2 to progression - 56 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 20 mg by mouth D 1, 3, 5, 15, 17, 19 panobinostat: Specified dose on specified days carfilzomib: Specified dose on specified days	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 45 mg/m^2 IV D 8, 9, 15, 16; cycle 2 to progression - 45 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 30 mg by mouth D 1, 3, 5, 15, 17, 19 panobinostat: Specified dose on specified days carfilzomib: Specified dose on specified days	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 56 mg/m^2 IV D 8, 9, 15, 16; cycle 2 to progression - 56 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 20 mg by mouth D 1, 3, 5, 15, 17, 19 panobinostat: Specified dose on specified days carfilzomib: Specified dose on specified days
Period Title: Overall Study
STARTED	4	3	3	3	3	3	31	30
COMPLETED	0	0	0	0	0	0	0	0
NOT COMPLETED	4	3	3	3	3	3	31	30

Baseline Characteristics

Arm/Group Title	Dose Level 1	Dose Level 2	Dose Level 3	Dose Level 4	Dose Level 5	Dose Level 6	Expansion Dose Level 4	Expansion Dose Level 6	Total
Arm/Group Description	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 27 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 27 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 20 mg D 1, 3, 5, 15, 17, 19 panobinostat: Specified dose on specified days carfilzomib: Specified dose on specified days	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 36 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 36 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 20 mg D 1, 3, 5, 15, 17, 19 panobinostat: Specified dose on specified days carfilzomib: Specified dose on specified days	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 45 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 45 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 20 mg D 1, 3, 5, 15, 17, 19 panobinostat: Specified dose on specified days carfilzomib: Specified dose on specified days	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 45 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 45 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 30 mg D 1, 3, 5, 15, 17, 19 panobinostat: Specified dose on specified days carfilzomib: Specified dose on specified days	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 56 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 56 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 30 mg D 1, 3, 5, 15, 17, 19	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 56 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 56 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 20 mg D 1, 3, 5, 15, 17, 19 panobinostat: Specified dose on specified days carfilzomib: Specified dose on specified days	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 45 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 45 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 30 mg D 1, 3, 5, 15, 17, 19 panobinostat: Specified dose on specified days carfilzomib: Specified dose on specified days	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 56 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 56 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 20 mg D 1, 3, 5, 15, 17, 19 panobinostat: Specified dose on specified days carfilzomib: Specified dose on specified days	Total of all reporting groups
Overall Participants	4	3	3	3	3	3	31	30	80
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63 (6.88)	54 (13.53)	70.7 (6.81)	56.3 (9.71)	71.3 (8.08)	67.3 (13.05)	65.7 (10.14)	65.1 (11.16)	65 (10.56)
Sex: Female, Male (Count of Participants)
Female	3 75%	2 66.7%	1 33.3%	1 33.3%	0 0%	1 33.3%	20 64.5%	12 40%	40 50%
Male	1 25%	1 33.3%	2 66.7%	2 66.7%	3 100%	2 66.7%	11 35.5%	18 60%	40 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	2 6.5%	2 6.7%	4 5%
Not Hispanic or Latino	4 100%	3 100%	3 100%	3 100%	3 100%	3 100%	23 74.2%	26 86.7%	68 85%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	6 19.4%	2 6.7%	8 10%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 3.3%	1 1.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	2 50%	1 33.3%	0 0%	0 0%	1 33.3%	0 0%	5 16.1%	2 6.7%	11 13.8%
White	2 50%	2 66.7%	3 100%	3 100%	2 66.7%	3 100%	24 77.4%	27 90%	66 82.5%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	2 6.5%	0 0%	2 2.5%
Pre-treatment ECOG (Count of Participants)
0 - Asymptomatic	2 50%	2 66.7%	2 66.7%	2 66.7%	2 66.7%	1 33.3%	12 38.7%	15 50%	38 47.5%
1 - Symptomatic but completely ambulatory	2 50%	1 33.3%	1 33.3%	1 33.3%	1 33.3%	2 66.7%	16 51.6%	15 50%	39 48.8%
2 - symptomatic, <50% in bed during the day	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	3 9.7%	00 0%	3 3.8%

Outcome Measures

1. Primary Outcome

Title	Number of Phase I Patients (Dose Level 1-6) Experiencing a Dose-Limiting Toxicity (DLT) to Determine the Optimal Dosage
Description	Using a traditional 3+3 dose escalation design, successive cohorts of subjects will receive a fixed dose level of the drug combination. The MTD is defined as the highest dose level at which ≤1 of 6 subjects experiences a dose-limiting toxicity (DLT) assessed by NCI CTCAE v4.0. DLT is defined as any of the following that are determined to be related to study treatment during Cycle 1: Grade 4 neutropenia for >7 days, Febrile neutropenia, Grade 3 thrombocytopenia with ≥ Grade 2 bleeding, Grade 4 thrombocytopenia > 7 days, ≥ Grade 2 neuropathy with uncontrolled pain, ≥ Grade 3 non-hematologic drug-related toxicity (excluding alopecia), despite optimal supportive care lasting >72 hours or requiring a dose reduction in the first cycle and Patients who are unable to receive 75% of the required doses of both agents secondary to toxicity. Number of Participants With such Dose Limiting Toxicities (DLT) at each level are reported here.
Time Frame	28 days from the start of study treatment

Outcome Measure Data

Analysis Population Description

Includes all Phase 1 patients receiving assigned study dosing

Arm/Group Title	Dose Level 1	Dose Level 2	Dose Level 3	Dose Level 4	Dose Level 5	Dose Level 6
Arm/Group Description	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 27 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 27 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 20 mg D 1, 3, 5, 15, 17, 19 panobinostat: Specified dose on specified days carfilzomib: Specified dose on specified days	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 36 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 36 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 20 mg D 1, 3, 5, 15, 17, 19 panobinostat: Specified dose on specified days carfilzomib: Specified dose on specified days	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 45 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 45 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 20 mg D 1, 3, 5, 15, 17, 19 panobinostat: Specified dose on specified days carfilzomib: Specified dose on specified days	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 45 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 45 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 30 mg D 1, 3, 5, 15, 17, 19 panobinostat: Specified dose on specified days carfilzomib: Specified dose on specified days	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 56 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 56 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 30 mg D 1, 3, 5, 15, 17, 19	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 56 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 56 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 20 mg D 1, 3, 5, 15, 17, 19 panobinostat: Specified dose on specified days carfilzomib: Specified dose on specified days
Measure Participants	4	3	3	3	3	3
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

2. Primary Outcome

Title	Phase II: Overall Response Rate
Description	Defined as the percentage of patients with confirmed complete response, very good partial response, or partial response (CR, VGPR, or PR) according to International Myeloma Working Group Uniform Response Criteria. CR=bone marrow contains ≤5% plasma cells; negative fixation on serum and urine; disappearance of soft tissue plasmacytomas. VGPR=≥90% reduction from baseline serum; urine M-protein level 100mg for 24h. PR=≥50% reduction from baseline in serum M-protein; disappearance of any soft tissue plasmacytomas.
Time Frame	up to 6 years

Outcome Measure Data

Analysis Population Description

All patients receiving dose level 4 and dose level 6 doses (both escalation and expansion phases combined) who had a post-baseline disease assessment per protocol were included in the analysis. 3 patients in dose level 4 and 1 patient in dose level 6 did not have a post-baseline assessment and were excluded from analysis.

Arm/Group Title	Dose Level 4 - Escalation and Expansion	Dose Level 6 - Escalation and Expansion
Arm/Group Description	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 45 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 45 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 30 mg D 1, 3, 5, 15, 17, 19	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 56 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 56 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 20 mg D 1, 3, 5, 15, 17, 19
Measure Participants	31	32
Number [percentage of participants]	74 1850%	84 2800%

3. Secondary Outcome

Title	Time-to-progression (TTP)
Description	Measured from date of first treatment until date of first documented progression as per International Myeloma Working Group Uniform Response Criteria. Progressive disease id defined as an increase of ≥ 25% from the nadir in at least one of the following criteria: serum M-protein (absolute increase must be ≥0.5 g/dL); urine M-protein (absolute increase must be ≥200 mg/24h) ; only in patients with non-measurable serum and urine M-protein levels: difference in involved and uninvolved FLC levels (absolute increase must be >10 mg/dL); only in patients with non-measurable serum and urine M-protein levels and non-measurable disease by FLC levels, bone marrow plasma cell percentage (absolute % must be ≥10%) 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 OR Development of hypercalcemia (corrected serum Ca >11.5mg/dL) for patients without hypercalcemia at baseline
Time Frame	up to 6 years

Outcome Measure Data

Analysis Population Description

All patients receiving dose level 4 and dose level 6 doses (both escalation and expansion phases combined) who had a post-baseline disease assessment per protocol were included in the analysis. 3 patients in dose level 4 and 1 patient in dose level 6 did not have a post-baseline assessment and were excluded from analysis.

Arm/Group Title	Dose Level 4 - Escalation and Expansion	Dose Level 6 - Escalation and Expansion
Arm/Group Description	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 45 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 45 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 30 mg D 1, 3, 5, 15, 17, 19	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 56 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 56 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 20 mg D 1, 3, 5, 15, 17, 19
Measure Participants	31	32
Median (95% Confidence Interval) [months]	11.6	11.7

4. Secondary Outcome

Title	Progression-free-survival (PFS)
Description	Measured from date of first protocol treatment until date of tumor progression or death as per International Myeloma Working Group Uniform Response Criteria. Progressive disease id defined as an increase of ≥ 25% from the nadir in at least one of the following criteria: serum M-protein (absolute increase must be ≥0.5 g/dL); urine M-protein (absolute increase must be ≥200 mg/24h) ; only in patients with non-measurable serum and urine M-protein levels: difference in involved and uninvolved FLC levels (absolute increase must be >10 mg/dL); only in patients with non-measurable serum and urine M-protein levels and non-measurable disease by FLC levels, bone marrow plasma cell percentage (absolute % must be ≥10%) 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 OR Development of hypercalcemia (corrected serum Ca >11.5mg/dL) for patients without hypercalcemia at baseline
Time Frame	up to 6 years

Outcome Measure Data

Analysis Population Description

All patients receiving dose level 4 and dose level 6 doses (both escalation and expansion phases combined) who had a post-baseline disease assessment per protocol were included in the analysis. 3 patients in dose level 4 and 1 patient in dose level 6 did not have a post-baseline assessment and were excluded from analysis.

Arm/Group Title	Dose Level 4 - Escalation and Expansion	Dose Level 6 - Escalation and Expansion
Arm/Group Description	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 45 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 45 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 30 mg D 1, 3, 5, 15, 17, 19	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 56 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 56 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 20 mg D 1, 3, 5, 15, 17, 19
Measure Participants	31	32
Median (95% Confidence Interval) [months]	12.1	10.3

5. Secondary Outcome

Title	Overall-survival (OS)
Description	Measured from time of first study treatment until date of death or date last known alive.
Time Frame	up to 6 years

Outcome Measure Data

Analysis Population Description

All patients receiving dose level 4 and dose level 6 doses (both escalation and expansion phases combined) who had a post-baseline disease assessment per protocol were included in the analysis. 3 patients in dose level 4 and 1 patient in dose level 6 did not have a post-baseline assessment and were excluded from analysis.

Arm/Group Title	Dose Level 4 - Escalation and Expansion	Dose Level 6 - Escalation and Expansion
Arm/Group Description	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 45 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 45 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 30 mg D 1, 3, 5, 15, 17, 19	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 56 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 56 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 20 mg D 1, 3, 5, 15, 17, 19
Measure Participants	31	32
Median (95% Confidence Interval) [months]	29.2	44.6

Adverse Events

Time Frame	From date of first treatment up to 6 years
Arm/Group Title	Dose Level 1		Dose Level 2		Dose Level 3		Dose Level 4		Dose Level 5		Dose Level 6		Expansion Dose Level 4		Expansion Dose Level 6
Arm/Group Description	Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 27 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 27 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 20 mg D 1, 3, 5, 15, 17, 19 panobinostat: Specified dose on specified days carfilzomib: Specified dose on specified days		Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 36 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 36 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 20 mg D 1, 3, 5, 15, 17, 19 panobinostat: Specified dose on specified days carfilzomib: Specified dose on specified days		Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 45 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 45 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 20 mg D 1, 3, 5, 15, 17, 19 panobinostat: Specified dose on specified days carfilzomib: Specified dose on specified days		Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 45 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 45 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 30 mg D 1, 3, 5, 15, 17, 19 panobinostat: Specified dose on specified days carfilzomib: Specified dose on specified days		Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 56 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 56 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 30 mg D 1, 3, 5, 15, 17, 19		Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 56 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 56 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 20 mg D 1, 3, 5, 15, 17, 19 panobinostat: Specified dose on specified days carfilzomib: Specified dose on specified days		Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 45 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 45 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 30 mg D 1, 3, 5, 15, 17, 19 panobinostat: Specified dose on specified days carfilzomib: Specified dose on specified days		Carfilzomib : cycle 1 - 20 mg/m^2 IV D1, 2 ; 56 mg/m^2 IV D 8, 9, 15, 16 cycle 2 to progression - 56 mg/m^2 IV D 1, 2, 8, 9, 15, 16 Panobinostat : cycle 1 and cycle 2 to progression - 20 mg D 1, 3, 5, 15, 17, 19 panobinostat: Specified dose on specified days carfilzomib: Specified dose on specified days
All Cause Mortality
	Dose Level 1		Dose Level 2		Dose Level 3		Dose Level 4		Dose Level 5		Dose Level 6		Expansion Dose Level 4		Expansion Dose Level 6
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/4 (75%)		0/3 (0%)		1/3 (33.3%)		1/3 (33.3%)		2/3 (66.7%)		2/3 (66.7%)		20/31 (64.5%)		12/30 (40%)
Serious Adverse Events
	Dose Level 1		Dose Level 2		Dose Level 3		Dose Level 4		Dose Level 5		Dose Level 6		Expansion Dose Level 4		Expansion Dose Level 6
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/4 (25%)		1/3 (33.3%)		0/3 (0%)		2/3 (66.7%)		1/3 (33.3%)		0/3 (0%)		16/31 (51.6%)		13/30 (43.3%)
Blood and lymphatic system disorders
Anaemia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/31 (0%)		1/30 (3.3%)
Haemolytic uraemic syndrome	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/31 (3.2%)		1/30 (3.3%)
Thrombocytopenia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/31 (0%)		0/30 (0%)
Thrombotic thrombocytopenic purpura	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/31 (0%)		1/30 (3.3%)
Cardiac disorders
Atrial fibrillation	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/31 (0%)		1/30 (3.3%)
Cardiac failure congestive	0/4 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		2/31 (6.5%)		1/30 (3.3%)
Supraventricular tachycardia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/31 (3.2%)		0/30 (0%)
Gastrointestinal disorders
Vomiting	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/31 (3.2%)		0/30 (0%)
Pancreatitis	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/31 (0%)		1/30 (3.3%)
Oesophageal obstruction	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/31 (0%)		1/30 (3.3%)
General disorders
Chest pain	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		2/31 (6.5%)		0/30 (0%)
Pyrexia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/31 (3.2%)		3/30 (10%)
Infections and infestations
Appendicitis	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/31 (3.2%)		0/30 (0%)
Bacteraemia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/31 (3.2%)		0/30 (0%)
Pneumonia	1/4 (25%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		3/31 (9.7%)		3/30 (10%)
Sepsis	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/31 (3.2%)		0/30 (0%)
Injury, poisoning and procedural complications
Contusion	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/31 (3.2%)		0/30 (0%)
Hip fracture	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/31 (3.2%)		0/30 (0%)
Multiple fractures	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/31 (3.2%)		0/30 (0%)
Metabolism and nutrition disorders
Dehydration	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		1/31 (3.2%)		0/30 (0%)
Fluid overload	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/31 (0%)		1/30 (3.3%)
Hypercalcaemia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/31 (0%)		1/30 (3.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Plasma cell myeloma	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/31 (0%)		0/30 (0%)
Nervous system disorders
Cerebrovascular accident	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/31 (0%)		0/30 (0%)
Headache	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/31 (3.2%)		0/30 (0%)
Migraine	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/31 (3.2%)		0/30 (0%)
Renal and urinary disorders
Acute kidney injury	0/4 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/31 (0%)		2/30 (6.7%)
Calculus urinary	1/4 (25%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/31 (0%)		0/30 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		1/31 (3.2%)		0/30 (0%)
Interstitial lung disease	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/31 (0%)		1/30 (3.3%)
Respiratory failure	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/31 (0%)		1/30 (3.3%)
Vascular disorders
Hypotension	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/31 (3.2%)		0/30 (0%)
Other (Not Including Serious) Adverse Events
	Dose Level 1		Dose Level 2		Dose Level 3		Dose Level 4		Dose Level 5		Dose Level 6		Expansion Dose Level 4		Expansion Dose Level 6
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		3/3 (100%)		3/3 (100%)		3/3 (100%)		3/3 (100%)		3/3 (100%)		31/31 (100%)		30/30 (100%)
Blood and lymphatic system disorders
Thrombocytopenia	4/4 (100%)		2/3 (66.7%)		2/3 (66.7%)		2/3 (66.7%)		3/3 (100%)		2/3 (66.7%)		23/31 (74.2%)		21/30 (70%)
Anaemia	3/4 (75%)		1/3 (33.3%)		1/3 (33.3%)		1/3 (33.3%)		3/3 (100%)		1/3 (33.3%)		16/31 (51.6%)		13/30 (43.3%)
Neutropenia	4/4 (100%)		3/3 (100%)		2/3 (66.7%)		2/3 (66.7%)		1/3 (33.3%)		2/3 (66.7%)		14/31 (45.2%)		8/30 (26.7%)
Leukopenia	2/4 (50%)		0/3 (0%)		2/3 (66.7%)		1/3 (33.3%)		1/3 (33.3%)		0/3 (0%)		8/31 (25.8%)		4/30 (13.3%)
Gastrointestinal disorders
Nausea	4/4 (100%)		3/3 (100%)		2/3 (66.7%)		3/3 (100%)		3/3 (100%)		2/3 (66.7%)		21/31 (67.7%)		19/30 (63.3%)
Diarrhoea	4/4 (100%)		3/3 (100%)		2/3 (66.7%)		3/3 (100%)		2/3 (66.7%)		2/3 (66.7%)		21/31 (67.7%)		15/30 (50%)
Vomiting	1/4 (25%)		2/3 (66.7%)		0/3 (0%)		1/3 (33.3%)		2/3 (66.7%)		1/3 (33.3%)		15/31 (48.4%)		15/30 (50%)
Abdominal Pain	1/4 (25%)		0/3 (0%)		1/3 (33.3%)		1/3 (33.3%)		0/3 (0%)		2/3 (66.7%)		5/31 (16.1%)		2/30 (6.7%)
Constipation	1/4 (25%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		3/31 (9.7%)		3/30 (10%)
Gastrooesophageal Reflux Disease	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		2/31 (6.5%)		2/30 (6.7%)
Abdominal Distension	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		1/31 (3.2%)		2/30 (6.7%)
General disorders
Fatigue	4/4 (100%)		1/3 (33.3%)		2/3 (66.7%)		3/3 (100%)		0/3 (0%)		2/3 (66.7%)		15/31 (48.4%)		16/30 (53.3%)
Pyrexia	2/4 (50%)		2/3 (66.7%)		2/3 (66.7%)		0/3 (0%)		1/3 (33.3%)		1/3 (33.3%)		11/31 (35.5%)		10/30 (33.3%)
Chills	2/4 (50%)		1/3 (33.3%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		2/3 (66.7%)		7/31 (22.6%)		7/30 (23.3%)
Oedema Peripheral	0/4 (0%)		1/3 (33.3%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		8/31 (25.8%)		10/30 (33.3%)
Asthenia	0/4 (0%)		0/3 (0%)		2/3 (66.7%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		4/31 (12.9%)		3/30 (10%)
Pain	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		5/31 (16.1%)		3/30 (10%)
Influenza Like Illness	1/4 (25%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		1/31 (3.2%)		2/30 (6.7%)
Immune system disorders
Seasonal Allergy	2/4 (50%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		2/31 (6.5%)		0/30 (0%)
Infections and infestations
Upper Respiratory Tract Infection	0/4 (0%)		1/3 (33.3%)		1/3 (33.3%)		1/3 (33.3%)		1/3 (33.3%)		1/3 (33.3%)		2/31 (6.5%)		9/30 (30%)
Sinusitis	0/4 (0%)		0/3 (0%)		1/3 (33.3%)		1/3 (33.3%)		0/3 (0%)		1/3 (33.3%)		6/31 (19.4%)		3/30 (10%)
Urinary Tract Infection	0/4 (0%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		4/31 (12.9%)		2/30 (6.7%)
Bronchitis	0/4 (0%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/31 (0%)		3/30 (10%)
Pneumonia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		2/31 (6.5%)		3/30 (10%)
Injury, poisoning and procedural complications
Fall	0/4 (0%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		2/31 (6.5%)		3/30 (10%)
Investigations
Blood Creatinine Increased	0/4 (0%)		1/3 (33.3%)		0/3 (0%)		1/3 (33.3%)		1/3 (33.3%)		1/3 (33.3%)		1/31 (3.2%)		6/30 (20%)
Platelet Count Decreased	0/4 (0%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		2/31 (6.5%)		5/30 (16.7%)
Alanine Aminotransferase Increased	0/4 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		4/31 (12.9%)		0/30 (0%)
Aspartate Aminotransferase Increased	0/4 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		3/31 (9.7%)		0/30 (0%)
Blood Alkaline Phosphatase	1/4 (25%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		2/31 (6.5%)		0/30 (0%)
Haemoglobin Decreased	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		3/31 (9.7%)		0/30 (0%)
Neutrophil Count Decreased	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		1/31 (3.2%)		2/30 (6.7%)
Metabolism and nutrition disorders
Decreased Appetite	2/4 (50%)		1/3 (33.3%)		2/3 (66.7%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		5/31 (16.1%)		7/30 (23.3%)
Dehydration	0/4 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		7/31 (22.6%)		5/30 (16.7%)
Hypokalaemia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		3/31 (9.7%)		5/30 (16.7%)
Hypocalcaemia	1/4 (25%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		2/31 (6.5%)		2/30 (6.7%)
Hyperkalaemia	0/4 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/31 (3.2%)		3/30 (10%)
Hyperphosphataemia	1/4 (25%)		2/3 (66.7%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/31 (0%)		2/30 (6.7%)
Hyperglycaemia	0/4 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		1/31 (3.2%)		1/30 (3.3%)
Hypomagnesaemia	0/4 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/31 (3.2%)		2/30 (6.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/4 (50%)		2/3 (66.7%)		1/3 (33.3%)		1/3 (33.3%)		0/3 (0%)		1/3 (33.3%)		3/31 (9.7%)		4/30 (13.3%)
Back Pain	0/4 (0%)		0/3 (0%)		1/3 (33.3%)		1/3 (33.3%)		0/3 (0%)		1/3 (33.3%)		6/31 (19.4%)		4/30 (13.3%)
Muscle Spasms	0/4 (0%)		1/3 (33.3%)		0/3 (0%)		2/3 (66.7%)		0/3 (0%)		0/3 (0%)		3/31 (9.7%)		6/30 (20%)
Pain In Extremity	0/4 (0%)		0/3 (0%)		1/3 (33.3%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		2/31 (6.5%)		3/30 (10%)
Musculoskeletal Chest Pain	0/4 (0%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		2/31 (6.5%)		2/30 (6.7%)
Myalgia	1/4 (25%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/31 (3.2%)		2/30 (6.7%)
Neck Pain	0/4 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		2/31 (6.5%)		2/30 (6.7%)
Musculoskeletal Pain	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		3/31 (9.7%)		1/30 (3.3%)
Nervous system disorders
Headache	2/4 (50%)		1/3 (33.3%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		10/31 (32.3%)		11/30 (36.7%)
Dizziness	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		4/31 (12.9%)		7/30 (23.3%)
Neuropathy Peripheral	0/4 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		4/31 (12.9%)		6/30 (20%)
Dysgeusia	2/4 (50%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		2/31 (6.5%)		1/30 (3.3%)
Psychiatric disorders
Insomnia	1/4 (25%)		1/3 (33.3%)		2/3 (66.7%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		4/31 (12.9%)		4/30 (13.3%)
Confusional State	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		2/31 (6.5%)		4/30 (13.3%)
Respiratory, thoracic and mediastinal disorders
Cough	3/4 (75%)		1/3 (33.3%)		2/3 (66.7%)		2/3 (66.7%)		2/3 (66.7%)		2/3 (66.7%)		6/31 (19.4%)		8/30 (26.7%)
Dyspnoea	1/4 (25%)		1/3 (33.3%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		9/31 (29%)		12/30 (40%)
Productive Cough	0/4 (0%)		1/3 (33.3%)		0/3 (0%)		1/3 (33.3%)		1/3 (33.3%)		0/3 (0%)		1/31 (3.2%)		5/30 (16.7%)
Oropharyngeal Pain	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		2/31 (6.5%)		5/30 (16.7%)
Nasal Congestion	0/4 (0%)		1/3 (33.3%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		2/31 (6.5%)		3/30 (10%)
Epistaxis	2/4 (50%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		2/31 (6.5%)		1/30 (3.3%)
Sinus Congestion	1/4 (25%)		1/3 (33.3%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		1/3 (33.3%)		0/31 (0%)		0/30 (0%)
Skin and subcutaneous tissue disorders
Rash	0/4 (0%)		1/3 (33.3%)		1/3 (33.3%)		1/3 (33.3%)		1/3 (33.3%)		0/3 (0%)		2/31 (6.5%)		4/30 (13.3%)
Pruritus	0/4 (0%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/31 (3.2%)		3/30 (10%)
Night Sweats	1/4 (25%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		1/31 (3.2%)		1/30 (3.3%)
Vascular disorders
Hypertension	1/4 (25%)		1/3 (33.3%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		1/3 (33.3%)		11/31 (35.5%)		5/30 (16.7%)
Hypotension	0/4 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		2/31 (6.5%)		4/30 (13.3%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.