Open-label Study of LCL161 Alone or With Cyclophosphamide in Relapsed/Refractory Multiple Myeloma

This study is currently recruiting participants.
Verified December 2013 by Mayo Clinic
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Peter L. Bergsagel, M.D., Mayo Clinic
ClinicalTrials.gov Identifier:
NCT01955434
First received: September 27, 2013
Last updated: December 4, 2013
Last verified: December 2013
  Purpose

This phase II trial studies how well Inhibitor of Apoptosis Proteins (IAP) antagonist LCL161 [also known as Second Mitochondria-derived Activator of Caspases (SMAC) mimetic LCL161] alone or with cyclophosphamide works in treating patients with relapsed or refractory multiple myeloma. Immunomodulatory therapies, such as LCL161, may stimulate the immune system in different ways to kill the cancer cells. 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, and can also help to modulate the immune response to cancer. It is not yet known whether giving LCL161 alone or with cyclophosphamide is more effective in treating multiple myeloma.


Condition Intervention Phase
Multiple Myeloma in Relapse
Refractory Plasma Cell Neoplasm
Drug: LCL161
Drug: cyclophosphamide
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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.

Resource links provided by NLM:


Further study details as provided by Mayo Clinic:

Primary Outcome Measures:
  • Proportion of confirmed overall responses [stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR)] with single agent LCL161 [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. 95% confidence intervals for the true success proportion will be calculated by the exact binomial method.


Secondary Outcome Measures:
  • Confirmed overall response rate with the addition of cyclophosphamide [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    Will be estimated by the number of patients who achieve a confirmed overall response at any time (with single agent LCL161 or LCL161 plus cyclophosphamide) divided by the number of evaluable patients. 95% confidence intervals for the true confirmed overall response rate will be calculated by the exact binomial method.

  • Overall survival [ Time Frame: From registration to death due to any cause, assessed up to 1 year ] [ Designated as safety issue: No ]
    The distribution of survival time will be estimated using the method of Kaplan-Meier.

  • Event-free survival [ Time Frame: From registration to disease progression while receiving LCL161 and cyclophosphamide, death due to any cause, or subsequent treatment for multiple myeloma, assessed up to 1 year ] [ Designated as safety issue: No ]
    The distribution of event-free survival will be estimated using the method of Kaplan-Meier.

  • Incidence of adverse events graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 30 days ] [ Designated as safety issue: Yes ]
    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.


Estimated Enrollment: 27
Study Start Date: November 2013
Estimated Study Completion Date: October 2017
Estimated Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: LCL161
Patients receive 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 also receive cyclophosphamide PO QD on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: LCL161
Given PO
Other Names:
  • LCL161
  • SMAC mimetic LCL161
  • IAP antagonist LCL161
Drug: cyclophosphamide
Given PO
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the confirmed overall response rate (>= partial response [PR]) to 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.

OUTLINE:

Patients receive 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 also receive cyclophosphamide PO QD on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 1 year.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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/μL
  • Untransfused platelet count >= 75,000/μL
  • 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
  • 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)
  • Willing to participate in associated biological specimen banking 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
  • 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). 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
  • Impaired cardiac function or clinically significant cardiac diseases.
  • 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
Please refer to this study by its ClinicalTrials.gov identifier: NCT01955434

Contacts
Contact: Mayo Clinic Clinical Trials Office 507-538-7623

Locations
United States, Arizona
Mayo Clinic in Arizona Recruiting
Scottsdale, Arizona, United States, 85259
Principal Investigator: Peter L. Bergsagel, M.D.         
United States, Florida
Mayo Clinic in Florida Not yet recruiting
Jacksonville, Florida, United States, 32224-9980
Principal Investigator: Asher A. Chanan-Khan, M.D.         
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Principal Investigator: Yi Lin, M.D., Ph.D.         
Sponsors and Collaborators
Mayo Clinic
Investigators
Study Chair: Peter L. Bergsagel, M.D. Mayo Clinic campus in Arizona
Principal Investigator: Asher Chanan-Khan, M.D. Mayo Clinic campus in Florida
  More Information

No publications provided

Responsible Party: Peter L. Bergsagel, M.D., Principal Investigator, Mayo Clinic
ClinicalTrials.gov Identifier: NCT01955434     History of Changes
Other Study ID Numbers: MC1381, NCI-2013-01276, MC1381, P30CA015083, CLCL161AUS01T
Study First Received: September 27, 2013
Last Updated: December 4, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Mayo Clinic:
Inhibitor of Apoptosis Proteins
SMAC peptide
Multiple Myeloma
Immunomodulator
Immunostimulant
LCL161
Cyclophosphamide

Additional relevant MeSH terms:
Plasmacytoma
Neoplasms
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists

ClinicalTrials.gov processed this record on April 15, 2014