Lenalidomide and Monoclonal Antibody With or Without Isotretinoin in Treating Younger Patients With Refractory or Recurrent Neuroblastoma

This study is currently recruiting participants.
Verified December 2013 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01711554
First received: October 18, 2012
Last updated: March 20, 2014
Last verified: December 2013

October 18, 2012
March 20, 2014
February 2013
July 2015   (final data collection date for primary outcome measure)
  • MTD defined as the highest dose level tested at which 0/6 or 1/6 patients experience dose-limiting toxicity (DLT) graded using the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) criteria, version 4.0 [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    All toxicities observed will be summarized in terms of type (organ affected or laboratory determination), severity (by NCI CTCAE), and attribution. Tables will be created to summarize theses toxicities and side effects by dose level and by course as well as with Kaplan-Meier plots (i.e. time to first delay or dose reduction) in order to assess the tolerability of the regime over multiple courses.
  • Recommended phase II dose [ Time Frame: 28 days ] [ Designated as safety issue: No ]
  • MTD defined as the highest dose level tested at which 0/6 or 1/6 patients experience dose-limiting toxicity (DLT) graded using the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) criteria, version 4.0 [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    All toxicities observed will be summarized in terms of type (organ affected or laboratory determination), severity (by NCI CTCAE), and attribution. Tables will be created to summarize theses toxicities and side effects by dose level and by course.
  • Recommended phase II dose [ Time Frame: 28 days ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01711554 on ClinicalTrials.gov Archive Site
  • Overall survival [ Time Frame: From start of lenalidomide until death for any reason or date that patient was last known to be alive if the patient is still alive, assessed up to 3 years ] [ Designated as safety issue: No ]
    Will be summarized with Kaplan-Meier plots.
  • Event-free survival [ Time Frame: From the start of treatment with lenalidomide until progression, clinical deterioration mandating that the patient terminate treatment or death due to any cause, assessed up to 3 years ] [ Designated as safety issue: No ]
    Will be summarized with Kaplan-Meier plots.
  • Changes in the levels of T cells, NK cells, monocytes, cytokines, and chemokines [ Time Frame: Baseline to up to 28 days ] [ Designated as safety issue: No ]
    These levels and the changes relative to baseline will be summarized by dose level by simple summary statistics: means (possibly after transformation) or medians, ranges, and standard deviations (if numbers and distribution permit). Scatter plots will be used to explore possible associations between the dose and day and toxicity experienced (as reflected in the maximum grade of toxicity experienced, infections or platelet recovery).
  • Changes in levels of HACA (or other genotype) and tumor response [ Time Frame: Baseline to up to 3 years ] [ Designated as safety issue: No ]
  • Pharmacokinetic determinations of lenalidomide [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    These will be summarized by dose level with simple summary statistics: means (possibly after transformation) or medians, ranges, and standard deviations (if numbers and distribution permit). Scatterplots will be used to explore possible associations between the dose and estimates of the pharmacokinetic parameters, and between the pharmacokinetic determinations and toxicity experienced (as reflected in the maximum grade of toxicity experienced or in clinical measurements).
  • Changes in TLDA scores [ Time Frame: Baseline to up to 3 years ] [ Designated as safety issue: No ]
    Standard descriptive summaries as well as scatterplots will be used.
  • Overall response [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: From start of lenalidomide until death for any reason or date that patient was last known to be alive if the patient is still alive, assessed up to 3 years ] [ Designated as safety issue: No ]
    Will be summarized with Kaplan-Meier plots.
  • Event-free survival [ Time Frame: From the start of treatment with lenalidomide until progression, clinical deterioration mandating that the patient terminate treatment or death due to any cause, assessed up to 3 years ] [ Designated as safety issue: No ]
    Will be summarized with Kaplan-Meier plots.
  • Changes in the levels of T cells, NK cells, monocytes, cytokines, and chemokines [ Time Frame: Baseline and up to 28 days ] [ Designated as safety issue: No ]
    These levels and the changes relative to baseline will be summarized by dose level by simple summary statistics: means (possibly after transformation) or medians, ranges, and standard deviations (if numbers and distribution permit). Scatter plots will be used to explore possible associations between the dose and day and toxicity experienced (as reflected in the maximum grade of toxicity experienced, infections or platelet recovery).
  • Changes in levels of HACA (or other genotype) and tumor response [ Time Frame: Baseline and up to 3 years ] [ Designated as safety issue: No ]
  • Pharmacokinetic determinations of lenalidomide [ Time Frame: Up to end of therapy ] [ Designated as safety issue: No ]
    These will be summarized by dose level with simple summary statistics: means (possibly after transformation) or medians, ranges, and standard deviations (if numbers and distribution permit). Scatterplots will be used to explore possible associations between the dose and estimates of the pharmacokinetic parameters, and between the pharmacokinetic determinations and toxicity experienced (as reflected in the maximum grade of toxicity experienced or in clinical measurements).
  • Changes in TLDA scores [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Standard descriptive summaries as well as scatterplots will be used.
  • Overall response [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Lenalidomide and Monoclonal Antibody With or Without Isotretinoin in Treating Younger Patients With Refractory or Recurrent Neuroblastoma
A Phase I Study of Lenalidomide and Anti-GD2 Mab Ch14.18 +/- Isotretinoin in Patients With Refractory/Recurrent Neuroblastoma

This phase I trial studies the side effects and best dose of lenalidomide when given together with monoclonal antibody with or without isotretinoin in treating younger patients with refractory or recurrent neuroblastoma. Drugs used in chemotherapy, such as lenalidomide and isotretinoin, work in different wants to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as monoclonal antibody Ch14.18, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving more than one drug (combination chemotherapy) together with monoclonal antibody therapy may kill more tumor cells.

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of lenalidomide in combination with fixed doses of ch14.18 (monoclonal antibody Ch14.18) given intravenously (IV) for four days (days 8-11) and isotretinoin given twice each day orally for 14 days (days 15-28) and repeated every 28 days to children with refractory or recurrent neuroblastoma.

II. To define the toxicities of lenalidomide administered in combination with ch14.18 and isotretinoin.

III. To describe the differences in immune function modulation between "low" versus "high" dose lenalidomide given with ch14.18 and isotretinoin.

SECONDARY OBJECTIVES:

I. To determine the pharmacokinetics of lenalidomide given in this combination regimen.

II. To determine the steady state pharmacokinetics of isotretinoin (day 28, course one) given in combination with lenalidomide.

III. To measure peak and trough levels of ch14.18 in patients receiving lenalidomide and to compare to historical controls of patients receiving ch14.18 in combination with interleukin 2 (IL-2) and granulocyte-macrophage colony-stimulating factor (GM-CSF).

IV. To describe the immunological effects of lenalidomide (T cells, natural killer [NK] cells, monocytes, cytokines, chemokines) within this three drug regimen.

V. To define the incidence and titers of human anti-chimeric antibody (HACA) on this regimen.

VI. To describe, within the context of a phase I study, the response rate to lenalidomide combined with ch14.18 and isotretinoin in patients with recurrent/refractory neuroblastoma.

VII. To determine, within the context of a Phase I study, if killer-cell immunoglobulin-like receptor (KIR) receptor-ligand mismatch or specific Fc gamma receptor (Fc gamma R) alleles are associated with anti-tumor response.

VIII. To quantify neuroblastoma tumor cell "load" using a 5-gene TaqMan Low Density Array (TLDA) assay in peripheral blood at study entry, following, with each disease evaluation and at end of therapy and bone marrow at study entry, with each response evaluation when bone marrow is sampled, and at end of therapy.

IX. To compare the toxicities of this regimen with the historical toxicity data from the Children's Oncology Group (COG) ANBL0032 and ANBL0931 studies of ch14.18 with IL-2, GM-CSF and isotretinoin.

X. To describe the tolerability and ability to give full doses of ch14.18 and lenalidomide over extended periods of time, i.e. in courses 6-12.

OUTLINE: This is a dose-escalation study of lenalidomide.

Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21, monoclonal antibody Ch14.18 IV over 10 hours on days 8-11, and isotretinoin PO twice daily (BID) on days 15-28 of dose levels 2-6. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Interventional
Phase 1
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Disseminated Neuroblastoma
  • Localized Unresectable Neuroblastoma
  • Recurrent Neuroblastoma
  • Regional Neuroblastoma
  • Stage 4S Neuroblastoma
  • Drug: lenalidomide
    Given PO
    Other Names:
    • CC-5013
    • IMiD-1
    • Revlimid
  • Biological: monoclonal antibody Ch14.18
    Given IV
    Other Names:
    • Ch14.18
    • MOAB Ch14.18
  • Drug: isotretinoin
    Given PO
    Other Names:
    • 13-CRA
    • Amnesteem
    • Cistane
    • Claravis
    • Sotret
  • Other: pharmacological study
    Correlative studies
    Other Name: pharmacological studies
  • Other: laboratory biomarker analysis
    Correlative studies
Experimental: Treatment (lenalidomide, monoclonal antibody, isotretinoin)
Patients receive lenalidomide PO QD on days 1-21, monoclonal antibody Ch14.18 IV over 10 hours on days 8-11, and isotretinoin PO BID on days 15-28 of dose levels 2-6. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Interventions:
  • Drug: lenalidomide
  • Biological: monoclonal antibody Ch14.18
  • Drug: isotretinoin
  • Other: pharmacological study
  • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
62
Not Provided
July 2015   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Patients must have a diagnosis of neuroblastoma either by histologic verification of neuroblastoma and/or demonstration of tumor cells in the bone marrow with increased urinary catecholamines
  • Patients must have high-risk neuroblastoma
  • Patients must have at least ONE of the following:

    • Recurrent/progressive disease at any time - regardless of response to frontline therapy
    • Refractory disease (i.e. less than a partial response to frontline therapy, including a minimum of 4 cycles of chemotherapy) AND has never had a relapse/progression
    • Persistent disease after at least a partial response to frontline therapy: i.e. patient has had a partial response to frontline therapy but still has residual disease AND has never had a relapse/disease progression; frontline response will be graded according to International Neuroblastoma Response Criteria (INRC)
  • Patients must have at least ONE of the following (excluding those patients entered in the expansion cohort who may be entered on study with no measurable or evaluable tumor if they have had a prior progression):

    • At least one metaiodobenzylguanidine (MIBG) avid bone site or diffuse MIBG uptake
    • Any amount of neuroblastoma tumor cells in the bone marrow based on routine morphology (with or without immunocytochemistry) in at least one sample from bilateral aspirates and biopsies; note: patients with < 10% tumor on all samples from bilateral bone marrow aspirates/biopsies are eligible, but will be considered separately in definitions of bone marrow response
    • At least one measurable soft tissue site on magnetic resonance imaging (MRI)/computed tomography (CT) scan that is MIBG or positron emission tomography (PET) avid (if patient known to be MIBG non-avid); measurable is defined as >= 10 mm in at least one dimension
    • At least one measurable soft tissue site on MRI/CT scan that is non-avid by MIBG and PET but that meets either one of the following criteria:

      • The lesion has been biopsied at any time point in the past and was documented to be neuroblastoma or ganglioneuroblastoma AND the lesion has enlarged since the immediate prior therapy by a minimum of 20% in at least one dimension
      • If the lesion is stable or smaller since the last prior therapy then a biopsy must be performed at least three weeks after the last day of the last prior therapy that shows neuroblastoma or ganglioneuroblastoma
  • Patients must have a life expectancy of at least 6 weeks
  • Lansky (=< 16 years) or Karnofsky (> 16 years) score of at least 50
  • Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to study enrollment
  • Patients must not have received the therapies indicated below for the specified time period prior to the first day of administration of protocol therapy on this study

    • Myelosuppressive chemotherapy: must have received last dose at least 2 weeks prior to protocol therapy; this includes cytotoxic agents given on a low dose metronomic regimen
    • Biologic (anti-neoplastic agent) (includes retinoids): must have received last dose at least 7 days prior to protocol therapy
    • Monoclonal antibodies: must have received last dose at least 7 days or 3 half-lives, whichever is longer, prior to protocol therapy
  • Radiation:

    • Patients must not have received radiation (small port) for a minimum of two weeks prior to protocol therapy; for patients with only one site of measurable or evaluable disease, radiation must not have been given to that site unless that site still has MIBG uptake or demonstrated clear progression after radiation, or a biopsy of the site demonstrated neuroblastoma at least 2 weeks after the last day of radiation
    • A minimum of 12 weeks prior to start of protocol therapy is required following large field radiation therapy (i.e. total body irradiation, craniospinal, whole abdominal, total lung, > 50% marrow space)
    • A minimum of 6 weeks must have elapsed prior to start of protocol therapy for other substantial bone marrow radiation
  • Stem Cell Transplant (SCT):

    • Patients are eligible 6 weeks after date of autologous stem cell infusion following myeloablative therapy (timed from first day of protocol therapy)
    • Patients are not eligible post allogeneic stem cell transplant
    • Patients who have received an autologous stem cell infusion to support non-myeloablative therapy (such as 131 iodine [I]-MIBG) are eligible at any time as long as they meet the other criteria for eligibility
  • A minimum of 6 weeks must have elapsed after 131I-MIBG therapy prior to start of protocol therapy
  • Prior anti-disialoganglioside (GD2) antibody, isotretinoin, or lenalidomide therapy:

    • Patients who have received prior anti-GD2 antibody therapy are eligible if they did not have tumor relapse/progression while receiving this therapy
    • Patients who have received either isotretinoin or lenalidomide are eligible, but not if they have received the two agents concomitantly
  • All cytokines or hematopoietic growth factors must be discontinued a minimum of 7 days prior to protocol therapy
  • Patients must not be receiving any other anti-cancer agents or radiotherapy at the time of study entry or while on study
  • Absolute phagocyte count (APC = neutrophils and monocytes): >= 1000/mm^3
  • Absolute neutrophil count: >= 750/mm^3
  • Platelet count: >= 50,000/mm^3, transfusion independent (no platelet transfusions within 1 week)
  • Hemoglobin >= 8.0 (may transfuse)
  • Patients with known bone marrow metastatic disease will be eligible for study as long as they meet hematologic function criteria; patients with marrow disease are not evaluable for hematologic toxicity
  • Age-adjusted serum creatinine =< 1.5 x normal for age or creatinine clearance or glomerular filtration rate (GFR) >= 60cc/min/1.73m^2

    • Age 1 month to < 6 months: 0.4 mg/dL for males and 0.4 mg/dL for females
    • Age 6 months to < 1 year: 0.5 mg/dL for males and 0.5 mg/dL for females
    • Age 1 to < 2 years: 0.6 mg/dL for males and 0.6 mg/dL for females
    • Age 2 to < 6 years: 0.8 mg/dL for males and 0.8 mg/dL for females
    • Age 6 to < 10 years: 1.0 mg/dL for males and 1.0 mg/dL for females
    • Age 10 to < 13 years: 1.2 mg/dL for males and 1.2 mg/dL for females
    • Age 13 to < 16 years: 1.5 mg/dL for males and 1.4 mg/dL for females
    • Age >= 16 years: 1.7 mg/dL for males and 1.4 mg/dL for females
  • =< grade 2 hematuria (criteria applicable only for dose levels that include isotretinoin) and =< grade 2 proteinuria
  • Total bilirubin =< 1.5 x upper limit of normal for age
  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 and serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 3 x upper limit of normal (note that for ALT, the upper limit of normal is defined as 45 U/L)
  • Sinusoidal obstruction syndrome (SOS) if present, must be stable or improving clinically
  • Cardiac function:

    • Normal ejection fraction (>= 55%) documented by either echocardiogram or radionuclide multi gated acquisition scan (MUGA) evaluation; OR
    • Normal fractional shortening (>= 27%) documented by echocardiogram
  • No dyspnea at rest
  • Serum triglyceride =< 300mg/dL (applicable only for dose levels that include isotretinoin) (note that a non-fasting triglyceride value could be obtained, if this is > 300 mg/dL then a fasting triglyceride should be obtained and patient will be eligible if the fasting level is =< 300 mg/dL)
  • =< grade 2 hypercalcemia (applicable only for dose levels that include cis retinoic acid [RA])
  • Skin toxicity =< grade 1
  • All post-menarchal females must have a negative beta-human chorionic gonadotropin (HCG); males and females of reproductive age and childbearing potential must use effective contraception for the duration of their participation; females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days and again within 24 hours prior to prescribing lenalidomide for cycle 1 and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide; FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy
  • Patients with other ongoing serious medical issues must be approved by the study chair prior to registration

Exclusion Criteria:

  • Quantitative serum b-HCG must be negative in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method; pregnant or breast-feeding women will not be entered on this study
  • Breast feeding women are not eligible
  • Patients who have an active or uncontrolled infection are excluded
  • Patients with a paraben allergy cannot take isotretinoin preparations containing this compound (ie Accutane, Sotret) but are eligible if they can take an alternate preparation without paraben; (applicable only for entry onto dose levels receiving isotretinoin)
  • Patients with a history of venous or arterial thrombosis personally before the age of 40 years unless associated with a central line
  • Patients with a history of prior central nervous system (CNS) metastases or skull lesions with intracranial extension will be required to have a head CT or MRI at study entry demonstrating no active CNS metastases; patients with skull metastases with associated intracranial soft tissue masses will remain eligible
  • Inability to swallow lenalidomide capsules whole; capsules of 13-isotretinoin may be opened
Both
up to 21 Years
No
Not Provided
United States,   Canada
 
NCT01711554
NCI-2012-02011, NCI-2012-02011, N2011-04, CDR0000741991, NANT N2011-04, NANT 2011-04, NANT N2011-04, P01CA081403
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Araz Marachelian New Approaches to Neuroblastoma Treatment (NANT)
National Cancer Institute (NCI)
December 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP