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

NCT01955434 | Completed Phase 2 Results DMC

• 4 other identifiers: MC1381NCI-2013-01276CLCL161AUS01TP30CA015083
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 3

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.

Conditions

Recurrent Plasma Cell Myeloma; Refractory Plasma Cell Myeloma

Outcome Measures

Primary Outcomes (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

  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.

  Up to 1 year

Secondary Outcomes (4)

• Combination Agent Response Rate

  Up to 1 year

• 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

• 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

• Overall Survival

  From registration to death due to any cause, assessed up to 1 year

Other Outcomes (5)

• Activating Mutations of the NFKB Pathway

  Up to 1 year

• Change in Patient-reported Outcomes (Quality of Life and Symptoms)

  Baseline up to 1 year

• Changes in Immune Cell Subsets

  Baseline up to 1 year

Study Arms (1)

Treatment (SMAC mimetic LCL161 and cyclophosphamide)

EXPERIMENTAL

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; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Other: Quality-of-Life Assessment; Drug: Smac Mimetic LCL161

Interventions

Cyclophosphamide DRUG

Given PO

Also known as: (-)-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

Treatment (SMAC mimetic LCL161 and cyclophosphamide)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (SMAC mimetic LCL161 and cyclophosphamide)

Pharmacological Study OTHER

Correlative studies

Treatment (SMAC mimetic LCL161 and cyclophosphamide)

Quality-of-Life Assessment OTHER

Ancillary studies

Also known as: Quality of Life Assessment

Treatment (SMAC mimetic LCL161 and cyclophosphamide)

Smac Mimetic LCL161 DRUG

Given PO

Also known as: LCL161

Treatment (SMAC mimetic LCL161 and cyclophosphamide)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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:

Sponsors & Collaborators

• Mayo Clinic: lead
• National Cancer Institute (NCI): collaborator

Study Sites (3)

Mayo Clinic in Arizona

Scottsdale, Arizona, 85259, United States

Location

Mayo Clinic in Florida

Jacksonville, Florida, 32224-9980, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

MeSH Terms

Conditions

Multiple Myeloma

Interventions

Cyclophosphamide; LCL161

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Results Point of Contact

• Title: P. Leif Bergsagel, MD
• Organization: Mayo Clinic

Bergsagel.leif@mayo.edu

480/301-8335

Study Officials

• Peter Bergsagel

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 27, 2013
• First Posted: October 7, 2013
• Study Start: November 1, 2013
• Primary Completion: June 9, 2016
• Study Completion: December 27, 2016
• Last Updated: September 10, 2019
• Results First Posted: February 7, 2018

Record last verified: 2016-08

Locations

US (3)