SMAC Mimetic LCL161 Alone or With Cyclophosphamide in Treating Patients With Relapsed or Refractory Multiple Myeloma

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT01955434
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 25
• Locations: 3
• Arm: 1
• Duration (Months): 37.8
• Patients Per Site: 8.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This phase II trial studies how well second mitochondrial-derived activator of caspases (SMAC) mimetic LCL161 alone or with cyclophosphamide works in treating patients with multiple myeloma that has returned or does not respond to treatment. Biological therapies, such as SMAC mimetic LCL161, may stimulate the immune system in different ways and stop cancer cells from growing. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. It is not yet known whether giving SMAC mimetic LCL161 alone or with cyclophosphamide is more effective in treating multiple myeloma.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Plasma Cell Myeloma; Refractory Plasma Cell Myeloma	Drug: Cyclophosphamide; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Other: Quality-of-Life Assessment; Drug: Smac Mimetic LCL161	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To evaluate the confirmed overall response rate (>= partial response [PR]) to LCL161 (SMAC mimetic LCL161), used as a single agent, in patients with relapsed multiple myeloma (MM).

SECONDARY OBJECTIVES:

1. To estimate the confirmed overall response rate to LCL161 in combination with cyclophosphamide, when cyclophosphamide is added to LCL161 for lack of response or progression.

2. To estimate the overall survival and event-free survival of patients treated with LCL161 in combination with cyclophosphamide, when cyclophosphamide is added to LCL161 for lack of response or progression.

3. To evaluate the tolerability of LCL161 alone and in combination with cyclophosphamide in patients with relapsed MM.

TERTIARY OBJECTIVES:

1. To determine degradation of cellular inhibitor of apoptosis protein-1 (cIAP1) in peripheral blood mononuclear cells (PBMC), changes in serum cytokines, and changes in immune cell subsets by flow cytometry.

2. To correlate the effect of LCL161 with the presence of activating mutations of the nuclear factor kappa beta (NFKB) pathway.

3. To evaluate the pharmacokinetics (PK) of LCL161 alone, and LCL161 in combination with cyclophosphamide.

4. To describe patient-reported health-related quality of life and symptoms.

OUTLINE:

Patients receive SMAC mimetic LCL161 orally (PO) once daily (QD) on days 1, 8, 15, and 22. Patients lacking a minor response by end of course 2 or partial response by end of course 4 may also receive cyclophosphamide PO QD on days 1, 8, 15, and 22 at the discretion of the treating physician. Patients taking cyclophosphamide with less than a 25% interval reduction in paraprotein receive SMAC mimetic LCL161 on days 2, 9, 16, and 23. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 6 months for 1 year.

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of LCL161 Alone and in Combination With Cyclophosphamide in Patients With Relapsed or Refractory Multiple Myeloma
• Study Start Date: Nov 1, 2013
• Actual Primary Completion Date: Jun 9, 2016
• Actual Study Completion Date: Dec 27, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (SMAC mimetic LCL161 and cyclophosphamide) Patients receive SMAC mimetic LCL161 PO QD on days 1, 8, 15, and 22. Patients lacking a minor response by end of course 2 or partial response by end of course 4 may also receive cyclophosphamide PO QD on days 1, 8, 15, and 22 at the discretion of the treating physician. Patients taking cyclophosphamide with less than a 25% interval reduction in paraprotein receive SMAC mimetic LCL161 on days 2, 9, 16, and 23. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Cyclophosphamide; Given PO; Other Names: (-)-Cyclophosphamide 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate Carloxan Ciclofosfamida Ciclofosfamide Cicloxal Clafen Claphene CP monohydrate CTX CYCLO-cell Cycloblastin Cycloblastine Cyclophospham Cyclophosphamid monohydrate Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclophosphanum Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan Neosar Revimmune Syklofosfamid WR- 138719 ; Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment ; Drug: Smac Mimetic LCL161; Given PO; Other Names: LCL161

Outcome Measures

Primary Outcome Measures

1. Confirmed Overall Response Rate (Stringent Complete Response [sCR], Complete Response [CR], Very Good Partial Response [VGPR], or Partial Response [PR]) With Single Agent SMAC Mimetic LCL161 [Up to 1 year]

   The primary endpoint of this study is the confirmed overall response rate with single agent LCL161 (prior to initiation of cyclophosphamide). A confirmed overall response is defined as sCR (CR as defined+Normal FLC ratio+Absence of clonal PCs by immunohistochemistry), CR (Negative immunofixation of serum and urine+Disappearance of any soft tissue plasmacytoma+<5% PCs in Bone Marrow+a normal FLC ratio), VGPR (Serum and urine M-component detectable by immunofixation but not on electrophoresis), or PR (If present at baseline, ≥ 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein or to <200 mg/24hrs) noted as the objective status on two consecutive evaluations while receiving single agent LCL161.The rate (percentage) of successes will be estimated by the number of successes divided by the total number of evaluable patients times 100. 95% confidence intervals for the true success percentage will be calculated by the exact binomial method.

Secondary Outcome Measures

1. Combination Agent Response Rate [Up to 1 year]

   The overall response rate (percentage) with the addition of cyclophosphamide will be estimated by the number of patients who achieve a confirmed overall response at any time (with SMAC mimetic LCL161 plus cyclophosphamide) divided by the number of evaluable patients times 100. 95% confidence intervals for the true confirmed overall response rate will be calculated by the exact binomial method.

2. Event-free Survival [From registration to disease progression while receiving SMAC mimetic LCL161 and cyclophosphamide, death due to any cause, or subsequent treatment for multiple myeloma, assessed up to 1 year]

   The event-free survival time is defined as the time from registration to disease progression while receiving LCL161 and cyclophosphamide, death due to any cause, or subsequent treatment for multiple myeloma. Date of progression will be defined as the date that the criteria for progressive disease were first met after initiation of cyclophosphamide. If a patient goes off study treatment and never received cyclophosphamide, they will be censored on the date they went off study treatment. If a patient initiates cyclophosphamide but later discontinues cyclophosphamide due to toxicity and continues LCL161 alone, disease progression on LCL161 alone will be considered an event in this case. The distribution of event-free survival will be estimated using the method of Kaplan-Meier.

3. Incidence of Toxicities Graded Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (All Treatment) [Up to 30 days after the last day of study drug treatment]

   The maximum grade for each type of adverse event, regardless of causality, will be recorded and reported for each patient, and frequency tables will be reviewed to determine adverse event patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. The percentage of patients with a maximum grade 3 or higher adverse event are reported below.

4. Overall Survival [From registration to death due to any cause, assessed up to 1 year]

   Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier.

Other Outcome Measures

1. Activating Mutations of the NFKB Pathway [Up to 1 year]

   Continuous biomarker levels will be explored in a graphical manner including mean plots and plots of change and percent change from baseline and other summary measures. Any potential relationships between the baseline level or change in the level of each biomarker and clinical outcome such as confirmed overall response, 6-month progression-free survival, and adverse event incidence will be further analyzed using Wilcoxon rank sum tests or logistic regression methods, as appropriate. Association between a mutation status and confirmed overall response will be assessed using a chi-squared test.

2. Change in Patient-reported Outcomes (Quality of Life and Symptoms) [Baseline up to 1 year]

   Scale score trajectories over time will be examined using stream plots and mean plots with standard deviation error bars overall. Changes from baseline at each cycle will be statistically tested using paired t-tests, and standardized response means (mean of the change from baseline scores at a given cycle, divided by the standard deviation of the change scores) will be interpreted (after applying Middel's adjustment) using Cohen's cut-offs. Correlation between outcomes will employ Pearson and/or Spearman correlations at individual time points.

3. Changes in Immune Cell Subsets [Baseline up to 1 year]

   Continuous biomarker levels will be explored in a graphical manner including mean plots and plots of change and percent change from baseline and other summary measures. Any potential relationships between the baseline level or change in the level of each biomarker and clinical outcome such as confirmed overall response, 6-month progression-free survival, and adverse event incidence will be further analyzed using Wilcoxon rank sum tests or logistic regression methods, as appropriate. Association between a mutation status and confirmed overall response will be assessed using a chi-squared test.

4. Changes in Serum Cytokines [Baseline up to 1 year]

   Continuous biomarker levels will be explored in a graphical manner including mean plots and plots of change and percent change from baseline and other summary measures. Any potential relationships between the baseline level or change in the level of each biomarker and clinical outcome such as confirmed overall response, 6-month progression-free survival, and adverse event incidence will be further analyzed using Wilcoxon rank sum tests or logistic regression methods, as appropriate. Association between a mutation status and confirmed overall response will be assessed using a chi-squared test.

5. Degradation of cIAP1 in PBMC [Baseline up to 1 year]

   Continuous biomarker levels will be explored in a graphical manner including mean plots and plots of change and percent change from baseline and other summary measures. Any potential relationships between the baseline level or change in the level of each biomarker and clinical outcome such as confirmed overall response, 6-month progression-free survival, and adverse event incidence will be further analyzed using Wilcoxon rank sum tests or logistic regression methods, as appropriate. Association between a mutation status and confirmed overall response will be assessed using a chi-squared test.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Relapsed or refractory multiple myeloma and has already received =< 4 standard treatment regimens; note: induction, transplant, consolidation, and maintenance is considered one regimen

• Have received prior therapy with an immunomodulatory agent, a proteosome inhibitor, and glucocorticoids

• Absolute neutrophil count (ANC) >= 1000/uL

• Untransfused platelet count >= 75,000/uL

• Aspartate aminotransferase (AST) =< 3 x upper limit of normal (ULN)

• Alanine aminotransferase (ALT) =< 3 x ULN

• Total bilirubin =< 1.5 mg/dL

• Serum creatinine =< 2.5 mg/dL

• Hemoglobin >= 8 g/dL

• Measurable disease of multiple myeloma as defined by at least ONE of the following:

• Serum monoclonal protein >= 1.0 g/dL

• = 200 mg of monoclonal protein in the urine on 24 hour electrophoresis

• Serum immunoglobulin free light chain >= 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio

• Monoclonal plasmacytosis >= 30% (evaluable disease)

• Measurable plasmacytoma that has not been radiated

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, 2

• Willing and able to comply with scheduled visits, treatment plan and laboratory tests

• Able to swallow and retain oral medication

• Provide informed written consent

• Negative serum pregnancy test done =< 7 days prior to registration, for women of childbearing potential only

• Willing to provide all biological specimens as required by the protocol for correlative research purposes

• Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)

• Mayo Clinic Arizona only: Willing to participate in associated biobanking study, 919-04; the patient must sign consent to enroll onto the mandatory companion biobanking study in order to participate in this treatment study

• Mayo Clinic Rochester and Florida only: Willing to participate in associated biobanking study, 521-93; the patient must sign consent to enroll onto the mandatory companion biobanking study in order to participate in this treatment study

Exclusion Criteria:

• Prior use of investigational drugs =< 14 days prior to registration

• Prior use of growth factors =< 14 days prior to registration

• Prior radiation therapy =< 14 days prior to registration

• Prior autologous stem cell transplant =< 12 weeks prior to registration

• Any of the following:

• Pregnant women

• Nursing women

• Women of childbearing potential who are unwilling to employ adequate contraception while receiving treatment on this study and for 4 months after stopping treatment on this study

• Men who are unwilling to use a condom (even if they have undergone a prior vasectomy) while having intercourse with any woman, while receiving treatment on this study and for 4 months after stopping treatment on this study NOTE: Postmenopausal women are allowed to participate in this study; women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago; in the case of oophorectomy alone, a woman is considered to be of not child bearing potential only when her reproductive status has been confirmed by follow-up hormone level assessment

• Prior allogeneic transplant of any kind

• Known active infection requiring parenteral or oral anti-infective treatment

• Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse follow-up evaluation

• Known human immunodeficiency virus (HIV) or active hepatitis B or C viral infection

• Active autoimmune/inflammatory conditions requiring ongoing immunosuppressive therapy

• Use of more than low dose corticosteroids (e.g., prednisone up to but no more than 10 mg PO QD or its equivalent) for symptom management and comorbid conditions, except for the following:

• Topical applications (e.g. rash)

• Inhaled sprays (e.g. obstructive airways diseases)

• Eye drops or local injections (e.g. intra-articular)

• Joint injections (e.g. arthritis) Doses of corticosteroid should be stable for at least 7 days prior to registration

• Any concurrent severe and/or uncontrolled medical conditions that could increase the patient's risk for toxicity while in the study or that could confound discrimination between disease- and study treatment-related toxicities

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

• History or presence of ventricular tachyarrhythmia

• Presence of unstable atrial fibrillation (ventricular response > 100 bpm) (NOTE: patients with stable atrial fibrillation are eligible, provided they do not meet any of the other cardiac exclusion criteria)

• Clinically significant resting bradycardia (< 50 bpm)

• Angina pectoris or acute myocardial infarction =< 3 months prior to registration

• Other clinically significant heart disease (e.g., symptomatic congestive heart failure; uncontrolled arrhythmia or hypertension; history of labile hypertension or poor compliance with an antihypertensive regimen)

• Currently receiving treatment with agents that are metabolized solely through cytochrome P450, family 3, subfamily A, polypeptide 4/5 (CYP3A4/5) and have a narrow therapeutic index or are strong cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) inhibitors; or are receiving treatment with agents that carry a risk for QT prolongation and are CYP3A substrates; caution should be used in patients taking other CYP2C8- or CYP3A4/5-interacting agents

• Impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of LCL161

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Arizona	Scottsdale	Arizona	United States	85259
2	Mayo Clinic in Florida	Jacksonville	Florida	United States	32224-9980
3	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Peter Bergsagel, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT01955434
• Other Study ID Numbers: MC1381; NCI-2013-01276; CLCL161AUS01T; MC1381; P30CA015083
• First Posted: Oct 7, 2013
• Last Update Posted: Sep 10, 2019
• Last Verified: Aug 1, 2016

• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Cyclophosphamide

Study Results

Participant Flow

Arm/Group Title	Treatment (SMAC Mimetic LCL161 and Cyclophosphamide)
Arm/Group Description	Patients receive SMAC mimetic LCL161 (1200 mg) PO QD on days 1, 8, 15, and 22. Patients lacking a minor response by end of course 2 or partial response by end of course 4 may also receive cyclophosphamide (500 mg) PO QD on days 1, 8, 15, and 22 at the discretion of the treating physician. Patients taking cyclophosphamide with less than a 25% interval reduction in paraprotein receive SMAC mimetic LCL161 on days 2, 9, 16, and 23. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	25
COMPLETED	25
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (SMAC Mimetic LCL161 and Cyclophosphamide)
Arm/Group Description	Patients receive SMAC mimetic LCL161 (1200 mg) PO QD on days 1, 8, 15, and 22. Patients lacking a minor response by end of course 2 or partial response by end of course 4 may also receive cyclophosphamide (500 mg) PO QD on days 1, 8, 15, and 22 at the discretion of the treating physician. Patients taking cyclophosphamide with less than a 25% interval reduction in paraprotein receive SMAC mimetic LCL161 on days 2, 9, 16, and 23. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Overall Participants	25
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	68.0
Sex: Female, Male (Count of Participants)
Female	9 36%
Male	16 64%
Region of Enrollment (Count of Participants)
United States	25 100%

Outcome Measures

1. Primary Outcome

Title	Confirmed Overall Response Rate (Stringent Complete Response [sCR], Complete Response [CR], Very Good Partial Response [VGPR], or Partial Response [PR]) With Single Agent SMAC Mimetic LCL161
Description	The primary endpoint of this study is the confirmed overall response rate with single agent LCL161 (prior to initiation of cyclophosphamide). A confirmed overall response is defined as sCR (CR as defined+Normal FLC ratio+Absence of clonal PCs by immunohistochemistry), CR (Negative immunofixation of serum and urine+Disappearance of any soft tissue plasmacytoma+<5% PCs in Bone Marrow+a normal FLC ratio), VGPR (Serum and urine M-component detectable by immunofixation but not on electrophoresis), or PR (If present at baseline, ≥ 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein or to <200 mg/24hrs) noted as the objective status on two consecutive evaluations while receiving single agent LCL161.The rate (percentage) of successes will be estimated by the number of successes divided by the total number of evaluable patients times 100. 95% confidence intervals for the true success percentage will be calculated by the exact binomial method.
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (SMAC Mimetic LCL161 and Cyclophosphamide)
Arm/Group Description	Patients receive SMAC mimetic LCL161 (1200 mg) PO QD on days 1, 8, 15, and 22. Patients lacking a minor response by end of course 2 or partial response by end of course 4 may also receive cyclophosphamide (500 mg) PO QD on days 1, 8, 15, and 22 at the discretion of the treating physician. Patients taking cyclophosphamide with less than a 25% interval reduction in paraprotein receive SMAC mimetic LCL161 on days 2, 9, 16, and 23. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	25
Number (95% Confidence Interval) [percentage of patients]	0

2. Secondary Outcome

Title	Combination Agent Response Rate
Description	The overall response rate (percentage) with the addition of cyclophosphamide will be estimated by the number of patients who achieve a confirmed overall response at any time (with SMAC mimetic LCL161 plus cyclophosphamide) divided by the number of evaluable patients times 100. 95% confidence intervals for the true confirmed overall response rate will be calculated by the exact binomial method.
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

Patients treated with combination of LCL161 and cyclophosphamide were included in this analysis.

Arm/Group Title	Treatment (SMAC Mimetic LCL161 and Cyclophosphamide)
Arm/Group Description	Patients receive SMAC mimetic LCL161 (1200 mg) PO QD on days 1, 8, 15, and 22. Patients lacking a minor response by end of course 2 or partial response by end of course 4 may also receive cyclophosphamide (500 mg) PO QD on days 1, 8, 15, and 22 at the discretion of the treating physician. Patients taking cyclophosphamide with less than a 25% interval reduction in paraprotein receive SMAC mimetic LCL161 on days 2, 9, 16, and 23. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	23
Number (95% Confidence Interval) [percentage of patients]	17.4

3. Secondary Outcome

Title	Event-free Survival
Description	The event-free survival time is defined as the time from registration to disease progression while receiving LCL161 and cyclophosphamide, death due to any cause, or subsequent treatment for multiple myeloma. Date of progression will be defined as the date that the criteria for progressive disease were first met after initiation of cyclophosphamide. If a patient goes off study treatment and never received cyclophosphamide, they will be censored on the date they went off study treatment. If a patient initiates cyclophosphamide but later discontinues cyclophosphamide due to toxicity and continues LCL161 alone, disease progression on LCL161 alone will be considered an event in this case. The distribution of event-free survival will be estimated using the method of Kaplan-Meier.
Time Frame	From registration to disease progression while receiving SMAC mimetic LCL161 and cyclophosphamide, death due to any cause, or subsequent treatment for multiple myeloma, assessed up to 1 year

Outcome Measure Data

Analysis Population Description

Patients treated with combination of LCL161 and cyclophosphamide were included in this analysis.

Arm/Group Title	Treatment (SMAC Mimetic LCL161 and Cyclophosphamide)
Arm/Group Description	Patients receive SMAC mimetic LCL161 (1200 mg) PO QD on days 1, 8, 15, and 22. Patients lacking a minor response by end of course 2 or partial response by end of course 4 may also receive cyclophosphamide (500 mg) PO QD on days 1, 8, 15, and 22 at the discretion of the treating physician. Patients taking cyclophosphamide with less than a 25% interval reduction in paraprotein receive SMAC mimetic LCL161 on days 2, 9, 16, and 23. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	23
Median (95% Confidence Interval) [months]	10.0

4. Secondary Outcome

Title	Incidence of Toxicities Graded Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (All Treatment)
Description	The maximum grade for each type of adverse event, regardless of causality, will be recorded and reported for each patient, and frequency tables will be reviewed to determine adverse event patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. The percentage of patients with a maximum grade 3 or higher adverse event are reported below.
Time Frame	Up to 30 days after the last day of study drug treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (SMAC Mimetic LCL161 and Cyclophosphamide)
Arm/Group Description	Patients receive SMAC mimetic LCL161 (1200 mg) PO QD on days 1, 8, 15, and 22. Patients lacking a minor response by end of course 2 or partial response by end of course 4 may also receive cyclophosphamide (500 mg) PO QD on days 1, 8, 15, and 22 at the discretion of the treating physician. Patients taking cyclophosphamide with less than a 25% interval reduction in paraprotein receive SMAC mimetic LCL161 on days 2, 9, 16, and 23. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	25
Anemia	24
Fatigue	16
Nausea	4.0
Platelet count decreased	12.0
Neutrophil count decreased	36.0
Lymphocyte count decreased	52.0
Vomiting	4.0
White blood cell decreased	20.0
Diarrhea	4.0
Rash maculo-papular	4.0
Hyperglycemia	12.0
Lymphocyte count increased	8
Syncope	12.0
Hyperuricemia	4.0
Hypotension	4.0
Lung infection	4.0
Pain in extremity	4.0
Sepsis	4.0
Uriticaria	4.0

5. Secondary Outcome

Title	Overall Survival
Description	Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier.
Time Frame	From registration to death due to any cause, assessed up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (SMAC Mimetic LCL161 and Cyclophosphamide)
Arm/Group Description	Patients receive SMAC mimetic LCL161 (1200 mg) PO QD on days 1, 8, 15, and 22. Patients lacking a minor response by end of course 2 or partial response by end of course 4 may also receive cyclophosphamide (500 mg) PO QD on days 1, 8, 15, and 22 at the discretion of the treating physician. Patients taking cyclophosphamide with less than a 25% interval reduction in paraprotein receive SMAC mimetic LCL161 on days 2, 9, 16, and 23. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	25
Median (95% Confidence Interval) [months]	NA

6. Other Pre-specified Outcome

Title	Activating Mutations of the NFKB Pathway
Description	Continuous biomarker levels will be explored in a graphical manner including mean plots and plots of change and percent change from baseline and other summary measures. Any potential relationships between the baseline level or change in the level of each biomarker and clinical outcome such as confirmed overall response, 6-month progression-free survival, and adverse event incidence will be further analyzed using Wilcoxon rank sum tests or logistic regression methods, as appropriate. Association between a mutation status and confirmed overall response will be assessed using a chi-squared test.
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Other Pre-specified Outcome

Title	Change in Patient-reported Outcomes (Quality of Life and Symptoms)
Description	Scale score trajectories over time will be examined using stream plots and mean plots with standard deviation error bars overall. Changes from baseline at each cycle will be statistically tested using paired t-tests, and standardized response means (mean of the change from baseline scores at a given cycle, divided by the standard deviation of the change scores) will be interpreted (after applying Middel's adjustment) using Cohen's cut-offs. Correlation between outcomes will employ Pearson and/or Spearman correlations at individual time points.
Time Frame	Baseline up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Other Pre-specified Outcome

Title	Changes in Immune Cell Subsets
Description	Continuous biomarker levels will be explored in a graphical manner including mean plots and plots of change and percent change from baseline and other summary measures. Any potential relationships between the baseline level or change in the level of each biomarker and clinical outcome such as confirmed overall response, 6-month progression-free survival, and adverse event incidence will be further analyzed using Wilcoxon rank sum tests or logistic regression methods, as appropriate. Association between a mutation status and confirmed overall response will be assessed using a chi-squared test.
Time Frame	Baseline up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Other Pre-specified Outcome

Title	Changes in Serum Cytokines
Description	Continuous biomarker levels will be explored in a graphical manner including mean plots and plots of change and percent change from baseline and other summary measures. Any potential relationships between the baseline level or change in the level of each biomarker and clinical outcome such as confirmed overall response, 6-month progression-free survival, and adverse event incidence will be further analyzed using Wilcoxon rank sum tests or logistic regression methods, as appropriate. Association between a mutation status and confirmed overall response will be assessed using a chi-squared test.
Time Frame	Baseline up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Other Pre-specified Outcome

Title	Degradation of cIAP1 in PBMC
Description	Continuous biomarker levels will be explored in a graphical manner including mean plots and plots of change and percent change from baseline and other summary measures. Any potential relationships between the baseline level or change in the level of each biomarker and clinical outcome such as confirmed overall response, 6-month progression-free survival, and adverse event incidence will be further analyzed using Wilcoxon rank sum tests or logistic regression methods, as appropriate. Association between a mutation status and confirmed overall response will be assessed using a chi-squared test.
Time Frame	Baseline up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	From baseline up to 30 days after last dose of study treatment
Adverse Event Reporting Description	CTCAE term (AE description) and grade: The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. Each CTCAE term in the current version is a unique representation of a specific event used for medical documentation and scientific analysis and is a single MedDRA Lowest Level Term (LLT)
Arm/Group Title	Treatment (SMAC Mimetic LCL161 and Cyclophosphamide)
Arm/Group Description	Patients receive SMAC mimetic LCL161 (1200 mg) PO QD on days 1, 8, 15, and 22. Patients lacking a minor response by end of course 2 or partial response by end of course 4 may also receive cyclophosphamide (500 mg) PO QD on days 1, 8, 15, and 22 at the discretion of the treating physician. Patients taking cyclophosphamide with less than a 25% interval reduction in paraprotein receive SMAC mimetic LCL161 on days 2, 9, 16, and 23. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Treatment (SMAC Mimetic LCL161 and Cyclophosphamide)
	Affected / at Risk (%)	# Events
Total	0/25 (0%)
Serious Adverse Events
	Treatment (SMAC Mimetic LCL161 and Cyclophosphamide)
	Affected / at Risk (%)	# Events
Total	11/25 (44%)
Immune system disorders
Cytokine release syndrome	2/25 (8%)	2
Infections and infestations
Lung infection	1/25 (4%)	1
Sepsis	1/25 (4%)	1
Investigations
Lymphocyte count decreased	4/25 (16%)	5
Metabolism and nutrition disorders
Hyperglycemia	1/25 (4%)	3
Hyperuricemia	1/25 (4%)	1
Musculoskeletal and connective tissue disorders
Pain in extremity	1/25 (4%)	1
Nervous system disorders
Syncope	2/25 (8%)	2
Skin and subcutaneous tissue disorders
Rash maculo-papular	1/25 (4%)	1
Urticaria	1/25 (4%)	1
Vascular disorders
Hypotension	1/25 (4%)	1
Other (Not Including Serious) Adverse Events
	Treatment (SMAC Mimetic LCL161 and Cyclophosphamide)
	Affected / at Risk (%)	# Events
Total	25/25 (100%)
Blood and lymphatic system disorders
Anemia	24/25 (96%)	133
Gastrointestinal disorders
Abdominal pain	6/25 (24%)	16
Constipation	11/25 (44%)	45
Diarrhea	11/25 (44%)	46
Dyspepsia	1/25 (4%)	2
Gastritis	1/25 (4%)	1
Nausea	19/25 (76%)	71
Vomiting	14/25 (56%)	45
General disorders
Edema limbs	7/25 (28%)	11
Fatigue	24/25 (96%)	134
Fever	8/25 (32%)	14
Malaise	1/25 (4%)	1
Immune system disorders
Cytokine release syndrome	2/25 (8%)	2
Infections and infestations
Sinusitis	1/25 (4%)	1
Investigations
Blood bilirubin increased	1/25 (4%)	1
Lymphocyte count decreased	14/25 (56%)	70
Lymphocyte count increased	3/25 (12%)	3
Neutrophil count decreased	17/25 (68%)	38
Platelet count decreased	18/25 (72%)	77
White blood cell decreased	12/25 (48%)	43
Metabolism and nutrition disorders
Anorexia	10/25 (40%)	18
Hyperglycemia	3/25 (12%)	5
Musculoskeletal and connective tissue disorders
Myalgia	1/25 (4%)	1
Nervous system disorders
Peripheral motor neuropathy	4/25 (16%)	37
Peripheral sensory neuropathy	17/25 (68%)	106
Presyncope	1/25 (4%)	1
Syncope	1/25 (4%)	1
Psychiatric disorders
Personality change	1/25 (4%)	1
Respiratory, thoracic and mediastinal disorders
Cough	11/25 (44%)	33
Dyspnea	11/25 (44%)	26
Pneumonitis	1/25 (4%)	1
Skin and subcutaneous tissue disorders
Pruritus	12/25 (48%)	22
Rash maculo-papular	9/25 (36%)	14

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.