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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Mayo Clinic
ClinicalTrials.gov Identifier:
NCT01955434
First received: September 27, 2013
Last updated: September 12, 2014
Last verified: September 2014
  Purpose

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 relapsed or refractory multiple myeloma. 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 Intervention Phase
Refractory Multiple Myeloma
Drug: SMAC mimetic LCL161
Drug: cyclophosphamide
Other: laboratory biomarker analysis
Other: pharmacological study
Other: quality-of-life assessment
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 SMAC mimetic 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 SMAC mimetic LCL161 or SMAC mimetic 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 SMAC mimetic 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.


Other Outcome Measures:
  • Degradation of cIAP1 in PBMC [ Time Frame: Baseline up to 1 year ] [ Designated as safety issue: No ]
    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.

  • Changes in serum cytokines [ Time Frame: Baseline up to 1 year ] [ Designated as safety issue: No ]
    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.

  • Changes in immune cell subsets [ Time Frame: Baseline up to 1 year ] [ Designated as safety issue: No ]
    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.

  • Activating mutations of the NFKB pathway [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    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.

  • Change in patient-reported outcomes (quality of life and symptoms) [ Time Frame: Baseline up to 1 year ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 27
Study Start Date: November 2013
Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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: SMAC mimetic LCL161
Given PO
Other Name: LCL161
Drug: cyclophosphamide
Given PO
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: quality-of-life assessment
Ancillary studies
Other Name: quality of life assessment

Detailed Description:

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.

  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/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 and Florida 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01955434

Locations
United States, Arizona
Mayo Clinic in Arizona
Scottsdale, Arizona, United States, 85259
United States, Florida
Mayo Clinic in Florida
Jacksonville, Florida, United States, 32224-9980
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Mayo Clinic
Investigators
Principal Investigator: Peter Bergsagel Mayo Clinic
  More Information

No publications provided

Responsible Party: Mayo Clinic
ClinicalTrials.gov Identifier: NCT01955434     History of Changes
Other Study ID Numbers: MC1381, NCI-2013-01276, CLCL161AUS01T, MC1381, P30CA015083
Study First Received: September 27, 2013
Last Updated: September 12, 2014
Health Authority: United States: Food and Drug Administration

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

ClinicalTrials.gov processed this record on November 20, 2014