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

PRIMARY OBJECTIVES:

I. 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:

I. 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.

II. 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.

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

TERTIARY OBJECTIVES:

I. 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.

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

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

IV. 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.

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