Irinotecan Hydrochloride and Temozolomide With Temsirolimus or Dinutuximab in Treating Younger Patients With Refractory or Relapsed Neuroblastoma

• ClinicalTrials.gov Identifier: NCT01767194
• Recruitment Status: Completed
• First Posted: January 14, 2013
• Results First Posted: November 18, 2019
• Last Update Posted: October 24, 2022
• Sponsor: National Cancer Institute (NCI)
• Collaborator: United Therapeutics
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: January 9, 2013
• First Posted Date: January 14, 2013
• Results First Submitted Date: June 24, 2019
• Results First Posted Date: November 18, 2019
• Last Update Posted Date: October 24, 2022
• Actual Study Start Date: February 12, 2013
• Actual Primary Completion Date: June 30, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 14, 2019)

• Percentage of Randomized Patients Who Are Responders [ Time Frame: Up to the first 6 cycles of treatment ]
  The percentage of patients who are responders will be tabulated, including a 95% confidence interval on the response rate. Responders are defined as patients who achieve a best overall response of complete response (CR), very good partial response (VGPR), or partial response (PR) per the International Neuroblastoma Response Criteria (INRC). Per INRC: CR= Disappearance of all target lesions. No evidence of tumor at any site; VGPR= >90% decrease of the disease measurement for CT/MRI target lesions. All pre-existing bone lesions with CR by MIBG; MIBG scan can be stable disease (SD) or CR in soft tissue lesions corresponding to lesions on CT/MRI. CR in bone marrow. No new sites of tumor; PR= >=30% decrease in the disease measurement for CT/MRI target lesions. Bone marrow with CR. MIBG with either PR/CR in bone lesions; MIBG may be SD or CR in soft tissue lesions corresponding to lesions on CT/MRI. Homovanillic acid (HVA)/Vanillylmandelic acid (VMA) may still be elevated.
• Percentage of Patients in the Dinutuximab Arm Who Are Responders [ Time Frame: Up to the first 6 cycles of treatment ]
  Percentage of patients who are responders to therapy with dinutuximab will be tabulated, including a 95% confidence interval on the response rate. Responders are defined as patients who achieve a best overall response of complete response (CR), very good partial response (VGPR), or partial response (PR) per the International Neuroblastoma Response Criteria (INRC). Per INRC: CR= Disappearance of all target lesions. No evidence of tumor at any site; VGPR= >90% decrease of disease measurement for CT/MRI target lesions. All pre-existing bone lesions with CR by MIBG; MIBG scan can be stable disease (SD) or CR in soft tissue lesions corresponding to lesions on CT/MRI. CR in bone marrow. No new sites of tumor; PR= ≥30% decrease in disease measurement for CT/MRI target lesions. Bone marrow with CR. MIBG with either PR/CR in bone lesions; MIBG may be SD or CR in soft tissue lesions corresponding to lesions on CT/MRI. Homovanillic acid (HVA)/ Vanillylmandelic acid (VMA) may still be elevated.

Original Primary Outcome Measures (submitted: January 10, 2013)

Proportion of Patients who are Responders [ Time Frame: Four months ]

Criteria (toxicity, feasibility, Progression Free Survival) will be used to answer the primary study objective. Patient's response is to be assessed for determination of the best overall response is after the completion of the first 6 cycles.

• Current Secondary Outcome Measures: Not Provided

Original Secondary Outcome Measures (submitted: January 10, 2013)

• Response Rate [ Time Frame: Four months ]
  Responders are defined patients who achieve better than a Partial Response. Patients with Progressive Disease prior to attaining better than a Partial Response will be considered failures for the analysis of response, and go off protocol therapy. In addition, patients who meet off protocol therapy criteria due to toxicity prior to attaining better than Partial Response will also be considered treatment failures. For a given patient, this primary endpoint is binary (responder, non-responder). Patient's response is to be assessed for determination of the best overall response is after the completion of the first 6 cycles.
• Progression-free survival [ Time Frame: 1 year ]
  An event is defined as a relapse, progressive disease, or death attributable to tumor or treatment. Time to event for Progression free survival will be calculated from the time of enrollment on the study until the occurrence of the first event or until the time of last contact if no event has occurred. Analysis of overall survival (event = death) will also be performed. Patient's response is to be assessed for determination of the best overall response is after the completion of the first 6 cycles.
• Toxicity [ Time Frame: Four months ]
  The toxicity endpoint will be defined as the occurrence of unacceptable toxicity per the CTCAE v4.0 toxicity grading scale. Patient's response is to be assessed for determination of the best overall response is after the completion of the first 6 cycles.
• Feasibility [ Time Frame: Four months ]
  Feasibility will be defined as the ability to maintain intended treatment with all agents (irinotecan, temozolomide and the experimental agent) without a dose reduction or going off protocol therapy for toxicity. Patient's response is to be assessed for determination of the best overall response is after the completion of the first 6 cycles.

Current Other Pre-specified Outcome Measures (submitted: November 14, 2019)

• Progression-free Survival [ Time Frame: Up to 3 years ]
  Kaplan-Meier method will be used to estimate progression-free survival. Progression-free survival will be defined as the time from enrollment to relapse, progressive disease, or death attributable to tumor or treatment.
• Overall Survival [ Time Frame: Up to 3 years ]
  Kaplan-Meier method will be used to estimate overall survival. Overall survival is defined as the time from enrollment on the study until death.
• Occurrence of Unacceptable Toxicities [ Time Frame: Up to 1 year ]
  The proportion of patients with at least one grade 3 or higher toxicity, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
• Ability to Maintain Intended Treatment Without a Dose Reduction or Going Off Protocol Therapy for Toxicity [ Time Frame: Up to 1 year ]
  The proportion of patients who required a dose modification or went off protocol therapy for toxicity will be calculated for each treatment group.
• Overall Response [ Time Frame: Up to the first 6 cycles of treatment ]
  The proportion of patients achieving each type of overall response (complete response, partial response, stable disease, progressive disease) will be calculated according to the International Neuroblastoma Response Criteria (INRC).

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Irinotecan Hydrochloride and Temozolomide With Temsirolimus or Dinutuximab in Treating Younger Patients With Refractory or Relapsed Neuroblastoma
• Official Title: A Phase II Randomized Trial of Irinotecan/Temozolomide With Temsirolimus (NSC# 683864) or Chimeric 14.18 Antibody (Ch14.18) (NSC# 764038) in Children With Refractory, Relapsed or Progressive Neuroblastoma
• Brief Summary: This randomized phase II trial studies how well irinotecan hydrochloride and temozolomide with temsirolimus or dinutuximab work in treating younger patients with neuroblastoma that has returned or does not respond to treatment. Drugs used in chemotherapy, such as irinotecan hydrochloride and temozolomide, 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. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as dinutuximab, may find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether giving irinotecan hydrochloride and temozolomide together with temsirolimus or dinutuximab is more effective in treating neuroblastoma.

Detailed Description

PRIMARY OBJECTIVES:

I. To identify whether temsirolimus or ch14.18 (dinutuximab) is the optimal therapeutic agent to consider for further testing in a future Phase III randomized trial for treatment of newly diagnosed high-risk neuroblastoma.

II. To determine the response rate of patients with relapsed, refractory or progressive neuroblastoma following treatment with irinotecan, temozolomide and ch14.18 (dinutuximab) and to compare this with the known response rate of patients treated with irinotecan and temozolomide alone.

EXPLORATORY OBJECTIVES:

I. To compare the response rates (RR) for patients receiving temsirolimus or ch14.18 (dinutuximab) in combination with irinotecan (irinotecan hydrochloride) and temozolomide.

II. To compare the progression free survival (PFS) and overall survival (OS) rates for patients receiving temsirolimus or ch14.18 (dinutuximab) in combination with irinotecan and temozolomide.

III. To compare the toxicities associated with temsirolimus or ch14.18 (dinutuximab) when combined with irinotecan and temozolomide in patients with refractory, relapsed or progressive neuroblastoma.

IV. To compare the ability to maintain intended dose intensity of all agents when temsirolimus or ch14.18 (dinutuximab) is combined with irinotecan and temozolomide in patients with refractory, relapsed or progressive neuroblastoma.

V. To determine the concordance between tumor responses as defined by standard International Neuroblastoma Response Criteria (INRC) versus response per the revised INRC.

VI. To study the clinical relevance of naturally occurring anti-glycan antibodies in patients receiving ch14.18 (dinutuximab) antibody.

VII. To study the clinical relevance of natural killer (NK) receptor natural cytotoxicity triggering receptor 3 (NKp30) isoforms in patients receiving ch14.18 (dinutuximab) antibody or temsirolimus.

VIII. To study the association between host factors and response to irinotecan, temozolomide and ch14.18 (dinutuximab).

IX. To characterize the tumor immune-microenvironment (gene expression; immune effector cells, activities and signaling molecules; immune target expression) following treatment with irinotecan, temozolomide and ch14.18 (dinutuximab).

X. To study the association between changes in the tumor immune-microenvironment (gene expression; immune effector cells, activities and signaling molecules; immune target expression) with response following treatment with irinotecan, temozolomide and ch14.18 (dinutuximab).

XI. To study the association between tumor genomic and transcriptomic aberrations as well as levels of circulating ganglioside (GD2) with response to irinotecan, temozolomide and ch14.18 (dinutuximab).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I (CLOSED TO ACCRUAL 06/17/2016): Patients receive temozolomide orally (PO) on days 1-5, irinotecan hydrochloride intravenously (IV) over 90 minutes on days 1-5, and temsirolimus IV over 30 minutes on days 1 and 8.

ARM II: Patients receive temozolomide PO on days 1-5, irinotecan hydrochloride over 90 minutes on days 1-5, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim subcutaneously (SC) or IV over 2 hours on days 6-12.

In both arms, treatment repeats every 21 days for up to 17 courses in the absence of disease progression or unacceptable toxicity.

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

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Ganglioneuroblastoma
• Recurrent Neuroblastoma

Intervention

• Biological: Dinutuximab
  Given IV
  Other Names:

  • Ch 14.18UTC
  • Ch14.18
  • MOAB Ch14.18
  • monoclonal antibody Ch14.18
  • Unituxin
• Drug: Irinotecan Hydrochloride
  Given IV
  Other Names:

  • Campto
  • Camptosar
  • Camptothecin 11
  • Camptothecin-11
  • CPT 11
  • CPT-11
  • Irinomedac
  • Irinotecan Hydrochloride Trihydrate
  • Irinotecan Monohydrochloride Trihydrate
  • U-101440E
• Other: Laboratory Biomarker Analysis
  Optional correlative studies
• Biological: Sargramostim
  Given SC or IV
  Other Names:

  • 23-L-Leucinecolony-Stimulating Factor 2
  • DRG-0012
  • Leukine
  • Prokine
  • rhu GM-CFS
  • Sagramostim
  • Sargramostatin
• Drug: Temozolomide
  Given PO
  Other Names:

  • CCRG-81045
  • Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-
  • M & B 39831
  • M and B 39831
  • Methazolastone
  • RP-46161
  • SCH 52365
  • Temcad
  • Temodal
  • Temodar
  • Temomedac
  • TMZ
• Drug: Temsirolimus
  Given IV
  Other Names:

  • CCI-779
  • CCI-779 Rapamycin Analog
  • Cell Cycle Inhibitor 779
  • Rapamycin Analog
  • Rapamycin Analog CCI-779
  • Torisel

Study Arms

• Experimental: Arm I (temozolomide, irinotecan hydrochloride, temsirolimus)
  CLOSED TO ACCRUAL 06/17/2016 Patients receive temozolomide PO on days 1-5, irinotecan hydrochloride IV over 90 minutes on days 1-5, and temsirolimus IV over 30 minutes on days 1 and 8.
  Interventions:

  • Drug: Irinotecan Hydrochloride
  • Other: Laboratory Biomarker Analysis
  • Drug: Temozolomide
  • Drug: Temsirolimus
• Experimental: Arm II (temozolomide, irinotecan hydrochloride, dinutuximab)
  Patients receive temozolomide PO on days 1-5, irinotecan hydrochloride over 90 minutes on days 1-5, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim SC or IV over 2 hours on days 6-12.
  Interventions:

  • Biological: Dinutuximab
  • Drug: Irinotecan Hydrochloride
  • Other: Laboratory Biomarker Analysis
  • Biological: Sargramostim
  • Drug: Temozolomide

Publications *

• Mody R, Yu AL, Naranjo A, Zhang FF, London WB, Shulkin BL, Parisi MT, Servaes SE, Diccianni MB, Hank JA, Felder M, Birstler J, Sondel PM, Asgharzadeh S, Glade-Bender J, Katzenstein H, Maris JM, Park JR, Bagatell R. Irinotecan, Temozolomide, and Dinutuximab With GM-CSF in Children With Refractory or Relapsed Neuroblastoma: A Report From the Children's Oncology Group. J Clin Oncol. 2020 Jul 1;38(19):2160-2169. doi: 10.1200/JCO.20.00203. Epub 2020 Apr 28.
• Mody R, Naranjo A, Van Ryn C, Yu AL, London WB, Shulkin BL, Parisi MT, Servaes SE, Diccianni MB, Sondel PM, Bender JG, Maris JM, Park JR, Bagatell R. Irinotecan-temozolomide with temsirolimus or dinutuximab in children with refractory or relapsed neuroblastoma (COG ANBL1221): an open-label, randomised, phase 2 trial. Lancet Oncol. 2017 Jul;18(7):946-957. doi: 10.1016/S1470-2045(17)30355-8. Epub 2017 May 23.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 17, 2018): 73
• Original Estimated Enrollment (submitted: January 10, 2013): 74
• Actual Study Completion Date: September 30, 2022
• Actual Primary Completion Date: June 30, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patients must have had histologic verification of neuroblastoma or ganglioneuroblastoma or demonstration of neuroblastoma cells in the bone marrow with elevated urinary catecholamines (i.e., > 2 x upper limit of normal [ULN]), at the time of initial diagnosis

• For the purposes of this study, aggressive multidrug chemotherapy is defined as chemotherapy including 2 or more agents that must include an alkylating agent and a platinum-containing compound; patients must have ONE of the following:

  • First episode of recurrent disease following completion of aggressive multi-drug frontline therapy
  • First episode of progressive disease during aggressive multi-drug frontline therapy
  • Primary resistant/refractory disease (less than partial response by INRC) detected at the conclusion of at least 4 cycles of aggressive multidrug induction chemotherapy on or according to a high-risk neuroblastoma protocol (examples include A3973, ANBL0532, ANBL09P1, etc.)

• Patients must have at least ONE of the following:

  • Measurable tumor on magnetic resonance imaging (MRI), computed tomography (CT) scan obtained within 3 weeks prior to study entry; measurable is defined as >= 10 mm in at least one dimension on spiral/helical CT that is metaiodobenzylguanidine (MIBG) avid or demonstrates increased fludeoxyglucose (FDG) uptake on positron emission tomography (PET) scan
  • MIBG scan obtained within 3 weeks prior to study entry with positive uptake at a minimum of one site; this site must represent disease recurrence after completion of therapy, progressive disease on therapy, or refractory disease during induction
  • Patients with resistant/refractory soft tissue disease that is not MIBG avid or does not demonstrate increased FDG uptake on PET scan must undergo biopsy to document the presence of viable neuroblastoma; biopsy is not required for patients who have new site of soft tissue disease (radiographic evidence of disease progression) regardless of whether progression occurs while receiving therapy or after completion of therapy
  • Note: Patients with elevated catecholamines (i.e., > 2 x ULN) only or bone marrow disease only are NOT eligible for this study
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age
• Patients must have received frontline therapy (including surgery, chemotherapy, autologous stem cell transplant [SCT] +/- MIBG, immunotherapy, radiotherapy, and retinoids) but may NOT have received second line chemotherapy for resistant/refractory, relapsed disease or progressive disease
• At least 14 days must have elapsed since completion of myelosuppressive therapy
• At least 7 days must have elapsed since the completion of therapy with a non-myelosuppressive biologic agent or retinoid
• No interim time prior to study entry is required following prior radiation therapy (RT) for non-target lesions; however, patients must not have received radiation for a minimum of 4 weeks prior to study entry at the site of any lesion that will be identified as a target lesion to measure tumor response; lesions that have been previously radiated cannot be used as target lesions unless there is radiographic evidence of progression at the site following radiation or a biopsy done following radiation shows viable neuroblastoma; palliative radiation is allowed to sites that will not be used to measure response during this study
• Patients are eligible >= 6 weeks after autologous stem cell transplants or stem cell infusions as long as hematologic and other eligibility criteria have been met
• Patients are eligible >= 6 weeks after therapeutic 131I-MIBG provided that all other eligibility criteria are met
• Subjects who have previously received anti-GD2 monoclonal antibodies for biologic therapy or for tumor imaging are eligible unless they have had progressive disease while receiving prior anti-GD2 therapy; subjects who have received autologous marrow infusions or autologous stem cell infusions that were purged using monoclonal antibody linked to beads, but no other form of anti-GD2 monoclonal antibody, are eligible
• Patients must not have received long-acting myeloid growth factors (e.g., Neulasta) within 14 days of entry on this study; seven days must have elapsed since administration of a short acting myeloid growth factor
• Peripheral absolute neutrophil count (ANC) >= 750/uL
• Platelet count >= 75,000/uL (transfusion independent)
• Patients known to have bone marrow involvement with neuroblastoma are eligible provided that minimum ANC and platelet count criteria are met but are not evaluable for hematological toxicity
• Creatinine clearance or estimated radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or

• A serum creatinine =< upper limit of normal (ULN) based on age/gender as follows:

  • Age 1 month to < 6 months: 0.4 for males, 0.4 for females
  • Age 6 months to < 1 year: 0.5 for males, 0.5 for females
  • Age 1 to < 2 years: 0.6 for males, 0.6 for females
  • Age 2 to < 6 years: 0.8 for males, 0.8 for females
  • Age 6 to < 10 years: 1 for males, 1 for females
  • Age 10 to < 13 years: 1.2 for males, 1.2 for females
  • Age 13 to < 16 years: 1.5 for males, 1.4 for females
  • Age >= 16 years: 1.7 for males, 1.4 for females
• Total bilirubin =< 1.5 x ULN for age AND
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5.0 x ULN for age (=< 225 U/L); for the purpose of this study, the ULN for SGPT is 45 U/L

• Adequate central nervous system function defined as:

  • Patients with a history of central nervous system (CNS) disease must have no clinical or radiological evidence of CNS disease at the time of study enrollment
  • Patients with seizure disorders may be enrolled if seizures are well controlled on anticonvulsants
  • CNS toxicity =< grade 2
• Shortening fraction of >= 27% by echocardiogram (ECHO) OR
• Ejection fraction >= 50% by ECHO or gated radionuclide study

• Adequate coagulation defined as:

  • Prothrombin time (PT) =< 1.2 x upper limit of normal

• Adequate pulmonary function defined as:

  • No evidence of dyspnea at rest, no exercise intolerance, no chronic oxygen requirement, and room air pulse oximetry > 94% if there is a clinical indication for pulse oximetry; normal pulmonary function tests in patients who are capable of cooperating with testing (including diffusion capacity of the lung of carbon monoxide [DLCO]) are required if there is a clinical indication for determination; for patients who do not have respiratory symptoms, full pulmonary function tests (PFTs) are NOT required

Exclusion Criteria:

• Men and women of childbearing potential and their partners must agree to use adequate contraception while enrolled on this study; based on the established teratogenic potential of alkylating agents, pregnant women will be excluded from this study; female patients who are lactating must agree to stop breastfeeding or will otherwise be excluded from this study; females of childbearing potential must have a negative pregnancy test to be eligible for this study
• Patients with elevated catecholamines (i.e., > 2 x ULN) only or bone marrow disease only are NOT eligible for this study
• Patients must have been off pharmacologic doses of systemic steroids for at least 7 days prior to enrollment; patients who require or are likely to require pharmacologic doses of systemic corticosteroids while receiving treatment on this study are ineligible; the only exception is for patients known to require 2 mg/kg or less of hydrocortisone (or an equivalent dose of an alternative corticosteroid) as premedication for blood product administration in order to avoid allergic transfusion reactions; the use of conventional doses of inhaled steroids for the treatment of asthma is permitted, as is the use of physiologic doses of steroids for patients with known adrenal insufficiency
• Patients must not have received enzyme-inducing anticonvulsants including phenytoin, phenobarbital, valproic acid, or carbamazepine for at least 7 days prior to study enrollment; patients receiving non-enzyme inducing anticonvulsants such as gabapentin or levetiracetam will be eligible
• Patients must not have been diagnosed with myelodysplastic syndrome or with any malignancy other than neuroblastoma
• Patients with symptoms of congestive heart failure are not eligible
• Patients must not have >= grade 2 diarrhea
• Patients must not have uncontrolled infection
• Patients with a history of grade 4 allergic reactions to anti-GD2 antibodies or reactions that required discontinuation of the anti-GD2 therapy are not eligible
• Patients with a significant intercurrent illness (any ongoing serious medical problem unrelated to cancer or its treatment) that is not covered by the detailed exclusion criteria and that is expected to interfere with the action of study agents or to significantly increase the severity of the toxicities experienced from study treatment are not eligible

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, New Zealand, Puerto Rico, United States

Administrative Information

• NCT Number: NCT01767194
• Other Study ID Numbers: NCI-2012-03125; NCI-2012-03125 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); CDR0000745188; ANBL1221; COG-ANBL1221; PANBL1221_A08PAMDREVW01; ANBL1221 ( Other Identifier: Children's Oncology Group ); ANBL1221 ( Other Identifier: CTEP ); U10CA180886 ( U.S. NIH Grant/Contract ); U10CA098543 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: National Cancer Institute (NCI)
• Original Responsible Party: Children's Oncology Group
• Current Study Sponsor: National Cancer Institute (NCI)
• Original Study Sponsor: Children's Oncology Group
• Collaborators: United Therapeutics

Investigators

• Principal Investigator: Rajen Mody; Children's Oncology Group

• PRS Account: National Cancer Institute (NCI)
• Verification Date: October 2022