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

Information source: National Cancer Institute (NCI)
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Ganglioneuroblastoma; Recurrent Neuroblastoma

Intervention: Dinutuximab (Biological); Irinotecan Hydrochloride (Drug); Laboratory Biomarker Analysis (Other); Sargramostim (Biological); Temozolomide (Drug); Temsirolimus (Drug)

Phase: Phase 2

Status: Suspended

Sponsored by: National Cancer Institute (NCI)

Official(s) and/or principal investigator(s):
Rajen Mody, Principal Investigator, Affiliation: Children's Oncology Group


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.

Clinical Details

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

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Proportion of patients who are responders defined as patients who achieve a >= partial response (PR) per the INRC as their best overall response

Secondary outcome:

Ability to maintain intended treatment with all agents (irinotecan hydrochloride, temozolomide and the experimental agent) without a dose reduction or going off protocol therapy for toxicity

Occurrence of unacceptable toxicities, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0

Overall response rate (complete response, PR, stable disease, progressive disease) according to the INRC

Overall survival

Progression-free survival, defined as a relapse, progressive disease, or death attributable to tumor or treatment

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. SECONDARY OBJECTIVES: I. To compare the response rates (RR) for patients receiving temsirolimus or ch14. 18 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 in combination with irinotecan and temozolomide. III. To compare the toxicities associated with temsirolimus or ch14. 18 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 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 antibody. VII. To study the clinical relevance of natural killer (NK) receptor natural cytotoxicity triggering receptor 3 (NKp30) isoforms in patients receiving ch14. 18 antibody or temsirolimus. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: 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 and irinotecan hydrochloride as in Arm I, 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.


Minimum age: N/A. Maximum age: N/A. Gender(s): Both.


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


- Primary resistant/refractory disease 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-disialoganglioside (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

- Serum lipids within acceptable range:

- Serum triglyceride level =< 300 mg/dL and serum cholesterol level =< 300 mg/dL;

If non-fasting values exceed these levels, lipid testing should be repeated in the fasting state

- 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 and temsirolimus, pregnant women will be excluded from this study; because of potential risks to breastfed infants due to drug metabolites that could be excreted in breast milk, 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 who have received prior therapy with an mammalian target of rapamycin (mTOR)

inhibitor in combination with cytotoxic chemotherapy are not eligible

- Patients with a history of significant allergic reactions attributed to compounds of

similar chemical or biologic composition to temsirolimus are not eligible

- 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

Locations and Contacts

Centre Hospitalier Universitaire de Quebec, Quebec G1V 4G2, Canada

Christchurch Hospital, Christchurch 8011, New Zealand

San Jorge Children's Hospital, San Juan 00912, Puerto Rico

Alberta Children's Hospital, Calgary, Alberta T3B 6A8, Canada

University of Alberta Hospital, Edmonton, Alberta T6G 2B7, Canada

Phoenix Childrens Hospital, Phoenix, Arizona 85016, United States

Arkansas Children's Hospital, Little Rock, Arkansas 72202-3591, United States

Starship Children's Hospital, Grafton, Auckland 1145, New Zealand

British Columbia Children's Hospital, Vancouver, British Columbia V6H 3V4, Canada

Southern California Permanente Medical Group, Downey, California 90242, United States

Loma Linda University Medical Center, Loma Linda, California 92354, United States

Children's Hospital Los Angeles, Los Angeles, California 90027, United States

Children's Hospital Central California, Madera, California 93636-8762, United States

Kaiser Permanente-Oakland, Oakland, California 94611, United States

Children's Hospital of Orange County, Orange, California 92868, United States

Lucile Packard Children's Hospital Stanford University, Palo Alto, California 94304, United States

University of California Davis Comprehensive Cancer Center, Sacramento, California 95817, United States

Rady Children's Hospital - San Diego, San Diego, California 92123, United States

UCSF Medical Center-Mission Bay, San Francisco, California 94158, United States

Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center, Denver, Colorado 80218, United States

Connecticut Children's Medical Center, Hartford, Connecticut 06106, United States

Yale University, New Haven, Connecticut 06520, United States

Alfred I duPont Hospital for Children, Wilmington, Delaware 19803, United States

Children's National Medical Center, Washington, District of Columbia 20010, United States

MedStar Georgetown University Hospital, Washington, District of Columbia 20007, United States

Golisano Children's Hospital of Southwest Florida, Fort Myers, Florida 33908, United States

University of Florida, Gainesville, Florida 32610, United States

Nemours Children's Clinic-Jacksonville, Jacksonville, Florida 32207, United States

Nicklaus Children's Hospital, Miami, Florida 33155, United States

University of Miami Miller School of Medicine-Sylvester Cancer Center, Miami, Florida 33136, United States

Florida Hospital Orlando, Orlando, Florida 32803, United States

Nemours Children's Hospital, Orlando, Florida 32827, United States

Nemours Children's Clinic - Pensacola, Pensacola, Florida 32504, United States

All Children's Hospital, Saint Petersburg, Florida 33701, United States

Saint Joseph's Hospital/Children's Hospital-Tampa, Tampa, Florida 33607, United States

Children's Healthcare of Atlanta - Egleston, Atlanta, Georgia 30322, United States

Memorial University Medical Center, Savannah, Georgia 31404, United States

Kapiolani Medical Center for Women and Children, Honolulu, Hawaii 96826, United States

Lurie Children's Hospital-Chicago, Chicago, Illinois 60611, United States

University of Chicago Comprehensive Cancer Center, Chicago, Illinois 60637, United States

University of Illinois, Chicago, Illinois 60612, United States

Advocate Children's Hospital-Oak Lawn, Oak Lawn, Illinois 60453, United States

Saint Jude Midwest Affiliate, Peoria, Illinois 61637, United States

Southern Illinois University School of Medicine, Springfield, Illinois 62702, United States

Riley Hospital for Children, Indianapolis, Indiana 46202, United States

Saint Vincent Hospital and Health Services, Indianapolis, Indiana 46260, United States

Blank Children's Hospital, Des Moines, Iowa 50309, United States

University of Iowa/Holden Comprehensive Cancer Center, Iowa City, Iowa 52242, United States

University of Kentucky/Markey Cancer Center, Lexington, Kentucky 40536, United States

Kosair Children's Hospital, Louisville, Kentucky 40202, United States

Children's Hospital New Orleans, New Orleans, Louisiana 70118, United States

Eastern Maine Medical Center, Bangor, Maine 04401, United States

CancerCare Manitoba, Winnipeg, Manitoba R3E 0V9, Canada

Johns Hopkins University/Sidney Kimmel Cancer Center, Baltimore, Maryland 21287, United States

Sinai Hospital of Baltimore, Baltimore, Maryland 21215, United States

Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States

C S Mott Children's Hospital, Ann Arbor, Michigan 48109, United States

Saint John Hospital and Medical Center, Detroit, Michigan 48236, United States

Wayne State University/Karmanos Cancer Institute, Detroit, Michigan 48201, United States

Michigan State University Clinical Center, East Lansing, Michigan 48824-7016, United States

Helen DeVos Children's Hospital at Spectrum Health, Grand Rapids, Michigan 49503, United States

Children's Hospitals and Clinics of Minnesota - Minneapolis, Minneapolis, Minnesota 55404, United States

University of Minnesota Medical Center-Fairview, Minneapolis, Minnesota 55455, United States

Mayo Clinic, Rochester, Minnesota 55905, United States

University of Mississippi Medical Center, Jackson, Mississippi 39216, United States

The Childrens Mercy Hospital, Kansas City, Missouri 64108, United States

Mercy Hospital Saint Louis, Saint Louis, Missouri 63141, United States

Washington University School of Medicine, Saint Louis, Missouri 63110, United States

Children's Hospital and Medical Center of Omaha, Omaha, Nebraska 68114, United States

University of Nebraska Medical Center, Omaha, Nebraska 68198, United States

Children's Specialty Center of Nevada II, Las Vegas, Nevada 89109, United States

Nevada Cancer Research Foundation CCOP, Las Vegas, Nevada 89106, United States

Summerlin Hospital Medical Center, Las Vegas, Nevada 89144, United States

Sunrise Hospital and Medical Center, Las Vegas, Nevada 89109, United States

University Medical Center of Southern Nevada, Las Vegas, Nevada 89102, United States

Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire 03756, United States

Hackensack University Medical Center, Hackensack, New Jersey 07601, United States

Morristown Medical Center, Morristown, New Jersey 07960, United States

UMDNJ - Robert Wood Johnson University Hospital, New Brunswick, New Jersey 08903, United States

University of New Mexico, Albuquerque, New Mexico 87102, United States

The Children's Hospital at Westmead, Westmead, New South Wales 2145, Australia

Albany Medical Center, Albany, New York 12208, United States

Montefiore Medical Center - Moses Campus, Bronx, New York 10467-2490, United States

Roswell Park Cancer Institute, Buffalo, New York 14263, United States

Winthrop University Hospital, Mineola, New York 11501, United States

The Steven and Alexandra Cohen Children's Medical Center of New York, New Hyde Park, New York 11040, United States

Columbia University Medical Center, New York, New York 10032, United States

University of Rochester, Rochester, New York 14642, United States

State University of New York Upstate Medical University, Syracuse, New York 13210, United States

New York Medical College, Valhalla, New York 10595, United States

Janeway Child Health Centre, Saint John's, Newfoundland and Labrador A1B 3V6, Canada

Mission Hospital-Memorial Campus, Asheville, North Carolina 28801, United States

University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States

Carolinas Medical Center/Levine Cancer Institute, Charlotte, North Carolina 28203, United States

Duke University Medical Center, Durham, North Carolina 27710, United States

IWK Health Centre, Halifax, Nova Scotia B3K 6R8, Canada

Children's Hospital Medical Center of Akron, Akron, Ohio 44308, United States

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, United States

Rainbow Babies and Childrens Hospital, Cleveland, Ohio 44106, United States

Nationwide Children's Hospital, Columbus, Ohio 43205, United States

Dayton Children's Hospital, Dayton, Ohio 45404, United States

The Toledo Hospital/Toledo Children's Hospital, Toledo, Ohio 43606, United States

University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, United States

McMaster Children's Hospital at Hamilton Health Sciences, Hamilton, Ontario L8N 3Z5, Canada

Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H 8L1, Canada

Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada

Legacy Emanuel Children's Hospital, Portland, Oregon 97227, United States

Oregon Health and Science University, Portland, Oregon 97239, United States

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States

Saint Christopher's Hospital for Children, Philadelphia, Pennsylvania 19134, United States

Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224, United States

Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec H3T 1C5, Canada

The Montreal Children's Hospital of the MUHC, Montreal, Quebec H3H 1P3, Canada

Lady Cilento Children's Hospital, South Brisbane, Queensland 4101, Australia

Palmetto Health Richland, Columbia, South Carolina 29203, United States

BI-LO Charities Children's Cancer Center, Greenville, South Carolina 29605, United States

Sanford USD Medical Center - Sioux Falls, Sioux Falls, South Dakota 57117-5134, United States

East Tennessee Childrens Hospital, Knoxville, Tennessee 37916, United States

Vanderbilt University/Ingram Cancer Center, Nashville, Tennessee 37232, United States

Dell Children's Medical Center of Central Texas, Austin, Texas 78723, United States

Medical City Dallas Hospital, Dallas, Texas 75230, United States

UT Southwestern/Simmons Cancer Center-Dallas, Dallas, Texas 75390, United States

Cook Children's Medical Center, Fort Worth, Texas 76104, United States

Covenant Children's Hospital, Lubbock, Texas 79410, United States

Primary Children's Hospital, Salt Lake City, Utah 84113, United States

University of Virginia Cancer Center, Charlottesville, Virginia 22908, United States

Childrens Hospital-King's Daughters, Norfolk, Virginia 23507, United States

Virginia Commonwealth University/Massey Cancer Center, Richmond, Virginia 23298, United States

Seattle Children's Hospital, Seattle, Washington 98105, United States

Providence Sacred Heart Medical Center and Children's Hospital, Spokane, Washington 99204, United States

Princess Margaret Hospital for Children, Perth, Western Australia 6008, Australia

University of Wisconsin Hospital and Clinics, Madison, Wisconsin 53792, United States

Marshfield Clinic, Marshfield, Wisconsin 54449, United States

Midwest Children's Cancer Center, Milwaukee, Wisconsin 53226, United States

Additional Information

Starting date: February 2013
Last updated: August 20, 2015

Page last updated: August 23, 2015

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