Lenalidomide and Dinutuximab with or without Isotretinoin in Treating Younger Patients with Refractory or Recurrent Neuroblastoma

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase IBiomarker/Laboratory analysis, Treatment21 and underNANT 2011-04
NCI-2012-02011, CDR0000741991, N2011-04, NANT 11-04, PNANT N2011-04_A14PAMDREVW01, NANT N2011-04, NCT01711554

Trial Description

Summary

This phase I trial studies the side effects and best dose of lenalidomide when given together with dinutuximab with or without isotretinoin in treating younger patients with neuroblastoma that does not respond to treatment or that has come back. 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, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as dinutuximab, may interfere with the ability of tumor cells to grow and spread. Giving more than one drug (combination chemotherapy) together with dinutuximab therapy may kill more tumor cells.

Further Study Information

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 (dinutuximab) 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 summarize, within the context of a phase I study, the event-free survival of patients with recurrent/refractory neuroblastoma or in complete response (CR) after progressing, and who are treated with lenalidomide combined with ch14.18 and isotretinoin.

VIII. 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.

IX. 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.

X. 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.

XI. 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, dinutuximab 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.

Eligibility Criteria

Inclusion Criteria:

Serum triglyceride =< 300 mg/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)

Age-adjusted serum creatinine =< 1.5 x normal for age or creatinine clearance or glomerular filtration rate (GFR) >= 60 cc/min/1.73 m^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

Patients must have at least ONE of the following (lesions may have received prior radiation therapy as long as they meet the other criteria listed below):

Bone disease

  • At least one metaiodobenzylguanidine (MIBG) avid bone site or diffuse MIBG uptake

*** For recurrent/progressive or refractory disease a biopsy is not required regardless of number of MIBG avid lesions

*** For persistent disease, if patient has only 1 or 2 MIBG avid lesions OR a Curie score of 1-2, then biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma in at least one site present at the time of enrollment (bone marrow, bone, or soft tissue) is required to be obtained at any time point prior to enrollment and two weeks subsequent to most recent prior therapy; if a patient has 3 or more MIBG avid lesions OR a Curie score of >= 3 then no biopsy is required for eligibility

  • If a tumor is known to be MIBG non-avid, then a patient must have at least one fludeoxyglucose (FDG)-positron emission tomography (PET) avid bone site present at the time of enrollment with biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma obtained at any time prior to enrollment and two weeks subsequent to most recent prior therapy

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

At least one soft tissue lesion that meets the criteria for a TARGET lesion as defined by:

  • SIZE: Lesion can be accurately measured in at least one dimension with a longest diameter >= 10 mm, or for lymph nodes >= 15 mm on short axis; lesions meeting size criteria will be considered measurable
  • In addition to size, a lesion needs to meet ONE of the following criteria:

*** MIBG avid; for patients with persistent disease only: if a patient has only 1 or 2 MIBG avid lesions OR a Curie score of 1-2, then biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma in at least one site present at time of enrollment (either bone marrow, bone and/or soft tissue) is required to be obtained at any time point prior to enrollment and at least two weeks subsequent to most recent prior therapy; if a patient has 3 or more MIBG avid lesions OR a Curie score of >= 3 then no biopsy is required for eligibility

*** FDG-PET avid (only if tumor is known to be MIBG non-avid); these patients must have had a biopsy confirming neuroblastoma and/or ganglioneuroblastoma in at least one FDG-PET avid site present at the time of enrollment done prior to enrollment and at least two weeks subsequent to the most recent prior therapy

*** Non-avid lesion (both MIBG and FDG-PET non-avid); these patients must have had a biopsy confirming neuroblastoma and/or ganglioneuroblastoma in at least one non-avid lesion present at the time of enrollment done prior to enrollment and at least two weeks subsequent to the most recent prior therapy

Patients with other ongoing serious medical issues must be approved by the study chair prior to registration

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

=< grade 2 hypercalcemia (applicable only for dose levels that include cis retinoic acid [RA])

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

Sinusoidal obstruction syndrome (SOS) if present, must be stable or improving clinically

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)

=< grade 2 hematuria (criteria applicable only for dose levels that include isotretinoin) and =< grade 2 proteinuria

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

Hemoglobin >= 8.0 (may transfuse)

Platelet count: >= 50,000/mm^3, transfusion independent (no platelet transfusions within 1 week)

Absolute neutrophil count: >= 750/mm^3

Patients must not be receiving any other anti-cancer agents or radiotherapy at the time of study entry or while on study

All cytokines or hematopoietic growth factors must be discontinued a minimum of 7 days prior to 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

A minimum of 6 weeks must have elapsed after 131I-MIBG therapy prior to start of protocol therapy

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

Radiation:

Patients must not have received radiation (small port) for a minimum of two weeks prior to protocol therapy

Except for patients with a history of progressive disease, patients whose only site(s) of disease have been radiated are eligible if at least one lesion meets at least one of the criteria listed in sites of disease above

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

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

Patients must have a life expectancy of at least 6 weeks

Patients with prior progressive disease who do not meet criteria above, are eligible as long as they have not been off treatment for > 3 months prior to enrollment on NANT 2011-04

Patients must have at least ONE of the following:

Recurrent/progressive disease at any time prior to enrollment - regardless of response to frontline therapy

Refractory disease: persistent sites of disease (after less than a partial response to frontline therapy, following a minimum of 4 cycles of induction therapy) AND patient has never had a relapse/progression

Persistent disease: persistent disease after achieving at least a partial response to frontline therapy after a minimum of 4 cycles of induction therapy and patient has never had a relapse/progression

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

Skin toxicity =< grade 1

No dyspnea at rest

Total bilirubin =< 1.5 x upper limit of normal for age

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 have high-risk neuroblastoma

Absolute phagocyte count (APC = neutrophils and monocytes): >= 1000/mm^3

Exclusion Criteria:

Patients with a history of prior central nervous system (CNS) metastases or skull lesions with intracranial extension will be required to have a head computed tomography (CT) or magnetic resonance imaging (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

Patients with a paraben allergy cannot take isotretinoin preparations containing this compound (i.e. Accutane, Sotret) but are eligible if they can take an alternate preparation without paraben; (applicable only for entry onto dose levels receiving isotretinoin)

Patients who have an active or uncontrolled infection are excluded

Breast feeding women are not eligible

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

Patient declines participation in NANT 2004-05; unless the institution has been granted special exemption from mandatory enrollment on NANT 2004-05 by the NANT Operations Center

Patients with a history of venous or arterial thrombosis personally before the age of 40 years unless associated with a central line

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

National Cancer Institute

  • National Cancer Institute
Araz Marachelian, Principal Investigator

Trial Sites

U.S.A.

California
Los Angeles

Children's Hospital Los Angeles

Araz Marachelian
Ph: 323-361-8573
Email: amarachelian@chla.usc.edu

Araz Marachelian
Principal Investigator

Palo Alto

Lucile Packard Children's Hospital Stanford University

Clare J. Twist
Ph: 650-723-5535
Email: clare.twist@stanford.edu

Clare J. Twist
Principal Investigator

San Francisco

UCSF Medical Center-Parnassus

Katherine Kurshan Matthay
Ph: 415-476-0603
Email: matthayk@peds.ucsf.edu

Katherine Kurshan Matthay
Principal Investigator

Colorado
Aurora

Children's Hospital Colorado

Margaret Ellen Macy
Ph: 720-777-8856
Email: Margaret.macy@childrenscolorado.org

Margaret Ellen Macy
Principal Investigator

Georgia
Atlanta

Children's Healthcare of Atlanta - Egleston

Kelly C. Goldsmith
Ph: 404-727-2655
Email: kgoldsm@emory.edu

Kelly C. Goldsmith
Principal Investigator

Illinois
Chicago

University of Chicago Comprehensive Cancer Center

Susan Lerner Cohn
Ph: 773-702-2571
Email: scohn@peds.bsd.uchicago.edu

Susan Lerner Cohn
Principal Investigator

Massachusetts
Boston

Boston Children's Hospital

Suzanne Shusterman
Ph: 617-632-4901
Email: suzanne_shusterman@dfci.harvard.edu

Suzanne Shusterman
Principal Investigator

Michigan
Ann Arbor

C S Mott Children's Hospital

Gregory A. Yanik
Ph: 734-746-3243
Email: gyanik@umich.edu

Gregory A. Yanik
Principal Investigator

New York
New York

Memorial Sloan-Kettering Cancer Center

Stephen S. Roberts
Ph: 212-639-4034
Email: robertss@mskcc.org

Stephen S. Roberts
Principal Investigator

Ohio
Cincinnati

Cincinnati Children's Hospital Medical Center

Brian David Weiss
Ph: 513-636-9863
Email: brian.weiss@cchmc.org

Brian David Weiss
Principal Investigator

Pennsylvania
Philadelphia

Children's Hospital of Philadelphia

Yael P. Mosse
Ph: 215-590-0965
Email: mosse@chop.edu

Yael P. Mosse
Principal Investigator

Texas
Fort Worth

Cook Children's Medical Center

Mary Meaghan Petty Granger
Ph: 682-885-4007
Email: mgranger@cookchildrens.org

Mary Meaghan Petty Granger
Principal Investigator

Washington
Seattle

Seattle Children's Hospital

Julie Ruggieri Park
Ph: 206-987-1947
Email: julie.park@seattlechildrens.org

Julie Ruggieri Park
Principal Investigator

Canada

Ontario
Toronto

Hospital for Sick Children

Sylvain Baruchel
Ph: 416-813-7795
Email: sylvain.baruchel@sickkids.ca

Sylvain Baruchel
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01711554

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.