Clinical Trials /

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

NCT01711554

Description:

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 ways 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.

Related Conditions:
  • Neuroblastoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Lenalidomide and Dinutuximab With or Without Isotretinoin in Treating Younger Patients With Refractory or Recurrent Neuroblastoma
  • Official Title: A Phase I Study of Lenalidomide and Anti-GD2 Mab Ch14.18 +/- Isotretinoin in Patients With Refractory/Recurrent Neuroblastoma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2012-02011
  • SECONDARY ID: NCI-2012-02011
  • SECONDARY ID: CDR0000741991
  • SECONDARY ID: N2011-04
  • SECONDARY ID: NANT 11-04
  • SECONDARY ID: NANT N2011-04
  • SECONDARY ID: NANT N2011-04
  • SECONDARY ID: P01CA081403
  • NCT ID: NCT01711554

Conditions

  • Recurrent Neuroblastoma
  • Refractory Neuroblastoma

Interventions

DrugSynonymsArms
DinutuximabCh 14.18UTC, Ch14.18, MOAB Ch14.18, monoclonal antibody Ch14.18, UnituxinTreatment (lenalidomide, dinutuximab, isotretinoin)
Isotretinoin13-cis retinoic acid, 13-cis-Retinoate, 13-cis-Retinoic Acid, 13-cis-Vitamin A Acid, 13-cRA, Absorica, Accure, Accutane, Amnesteem, cis-Retinoic Acid, Cistane, Claravis, Isotretinoinum, Isotrex, Isotrexin, Myorisan, Neovitamin A, Neovitamin A Acid, Oratane, Retinoicacid-13-cis, Ro 4-3780, Ro-4-3780, Roaccutan, Roaccutane, Roacutan, Sotret, ZENATANETreatment (lenalidomide, dinutuximab, isotretinoin)
LenalidomideCC-5013, CC5013, CDC 501, RevlimidTreatment (lenalidomide, dinutuximab, isotretinoin)

Purpose

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 ways 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.

Detailed Description

      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 dinutuximab (ch14.18) and isotretinoin given
      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
      intravenously (IV) over 10 hours on days 8-11, and isotretinoin PO twice daily (BID) on days
      15-28. 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (lenalidomide, dinutuximab, isotretinoin)ExperimentalPatients receive lenalidomide PO QD on days 1-21, dinutuximab IV over 10 hours on days 8-11, and isotretinoin PO BID on days 15-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
  • Dinutuximab
  • Isotretinoin
  • Lenalidomide

Eligibility Criteria

        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 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 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 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 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

               -  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

          -  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) >= 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

          -  =< 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 =< 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)

          -  =< 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 (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 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 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

          -  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
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose defined as the highest dose level tested at which 0/6 or 1/6 patients experience dose-limiting toxicity (DLT) graded using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) criteria, version 4.0
Time Frame:Up to 28 days
Safety Issue:
Description: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 these 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.

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:Will be summarized with Kaplan-Meier plots.
Measure: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, whichever occurs first, assessed up to 3 years
Safety Issue:
Description:Will be summarized with Kaplan-Meier plots.
Measure:Changes in the levels of T cells, natural killer (NK) cells, monocytes, cytokines, and chemokines
Time Frame:Baseline to up to 28 days
Safety Issue:
Description: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). Scatterplots 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).
Measure:Changes in levels of HACA (or other genotype) and tumor response
Time Frame:Baseline to up to 3 years
Safety Issue:
Description: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). Scatterplots 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).
Measure:Pharmacokinetic determinations of lenalidomide
Time Frame:Baseline, at 60 and 90 minutes, at 2, 6, 24 hours and days 7 and 22 after last dose of lenalidomide in course 1
Safety Issue:
Description: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).
Measure:Changes in TaqMan low density array (TLDA) scores
Time Frame:Baseline to up to 3 years
Safety Issue:
Description:Standard descriptive summaries as well as scatterplots will be used. The association between the changes in TLDA scores and overall tumor response will also be summarized graphically and quantitatively. Changes (from baseline) in the TLDA scores over the course of treatment will be plotted and summarized by dose level and course.
Measure:Overall response
Time Frame:Up to 3 years
Safety Issue:
Description:The association between the changes in TLDA scores and overall tumor response will be summarized graphically and quantitatively.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

March 8, 2021