Combination Therapy of Antibody Hu3F8 With Granulocyte- Macrophage Colony Stimulating Factor (GM-CSF) in Patients With Relapsed/Refractory High-Risk Neuroblastoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT01757626
Recruitment Status : Recruiting
First Posted : December 31, 2012
Last Update Posted : October 8, 2018
Y-mAbs Therapeutics
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center

Brief Summary:
The purpose of this study is to find out if an antibody called Humanized 3F8 (Hu3F8) combined with granulocyte- macrophage colony stimulating factor (GM-CSF) is safe for treating neuroblastoma.

Condition or disease Intervention/treatment Phase
Neuroblastoma Biological: Hu3F8 With GM-CSF Phase 1 Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 224 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Study of Combination Therapy of Antibody Hu3F8 With Granulocyte- Macrophage Colony Stimulating Factor (GM-CSF) in Patients With Relapsed/Refractory High-Risk Neuroblastoma
Study Start Date : December 2012
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Neuroblastoma

Arm Intervention/treatment
Experimental: Hu3F8 with GM-CSF
The phase I single arm trial assesses escalating doses of iv hu3F8 (days 1, 3, 5) in the presence of sc GM-CSF (day -4 through 5). These 3 doses of hu3F8 and 10 days of GM-CSF constitute a treatment cycle. The expansion phase II single arm trial assesses the anti-NB activity of 3 groups of patients: Group 1 patients have primary refractory disease (no prior relapse but incomplete response to treatment) in BM as documented by histology and/or 123I-MIBG scan. Group 2 patients are in >2nd CR/VGPR and at high risk for another relapse. Group 3 patients have secondary refractory disease (prior relapse and incomplete response to retrieval therapy) in BM as documented by histology and/or 123I-MIBG scan. Ph II: Groups 1 & 3 pts can continue to get cycles every 1-2 months for up to 24 months from study enrollment or until they receive 5 cycles after a major response (CR or PR) is achieved.
Biological: Hu3F8 With GM-CSF
Ph I: 1 cycle consists of treatment with hu3F8 for 3 days (day 1, 3 & 5). GM-CSF starts 5 days in advance of each hu3F8 cycle at 250 mcg/m^2/day (day -4 to day 0), & at 500 mcg/m^2/day x 5 days (day 1 to day 5). Hu3F8 cycles are 5 days. Ph II pts may receive treatment on a modified schedule of 3 doses of IV hu3F8 over a maximum of 10 days, as needed. With modified schedules of hu3F8, GM-CSF will be administered at 250 mcg/m2/day x5 days before the 1st dose of hu3F8, as with the standard schedule, but then GM-CSF at 500 mcg/m2/day will be administered on day of the 1st dose of hu3F8, on the day before and on the day of the 2nd dose of hu3F8, and on the day before and on the day of the 3rd dose of hu3F8. Cycles are repeated at 2-4 week intervals between 1st days of hu3F8, through 4 cycles. Pts who complete 4 cycles of treatment w/o complications or disease progression have the option of continuing treatment for up to 24 months from their 1st dose of hu3F8.

Primary Outcome Measures :
  1. maximum tolerated dosage [ Time Frame: 1 year ]
    hu3F8 when combined with GM-CSF. DLT is defined after 1 cycle. Seventeen dosage levels of hu3F8 will be tested with three to six patients at each dosage level.

  2. assess the toxicity [ Time Frame: 1 year ]
    of the humanized anti GD2 antibody hu3F8 when combined with Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) in patients with high risk neuroblastoma. All observed adverse events, regardless of treatment group or suspected causal relationship to study drug will be recorded. Adverse events will be identified and graded using the Common Toxicity Criteria Version 4.0

Secondary Outcome Measures :
  1. pharmacokinetics of hu3F8 [ Time Frame: 1 year ]
    (Phase I) when combined with GM-CSF. Pharmacokinetics will be measured by serial blood sampling following the first two iv doses of hu3F8 as listed in Table 3. Serum hu3F8 will be measured pre-infusion and at time pre- (within an hour before hu3F8), 5 min, 3h, 6-8h, 24h, 48h, 72h, 96, 120h, 168h 216h and 264h after the first infusion of hu3F8 during cycle1 and, whenever possible, peak hu3F8 level at pre- and ~5 minutes post-infusion will also be measured for each dose of hu3F8 in subsequent cycles .

  2. assess activity of hu3F8 plus GM-CSF against NB [ Time Frame: 1 year ]
    Another secondary objective is to assess the anti-tumor activity of hu3F8 against NB and other GD2-positive tumors. Anti-tumor activity will be measured by international neuroblastoma response criteria (INRC).

  3. quantitate the response of marrow NB [ Time Frame: 1 year ]
    will be measured using quantitative Reverse transcription-PCR (qRTPCR) and its relationship with dosage of hu3F8 explored.

Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Diagnosis of NB as defined by a) histopathology (confirmed by the MSKCC Department of Pathology), or b) BM metastases or MIBG-avid lesion(s) plus high urine catecholamine levels.
  • Patients must have high-risk NB (including MYCNamplified stage 2/3/4/4S of any age and MYCN-nonamplified stage 4 in patients greater than 18 months of age) AND:
  • Phase I: Patients must have refractory or relapsed NB, resistant to standard therapy*.

    *For NB, standard therapy includes intensive induction chemotherapy, followed by a variety of consolidation or salvage therapies, depending on response.

  • Phase II: Patients must have primary or secondary refractory disease in BM, defined as morphologic evidence of NB in BM and/or abnormal 123I-MIBG uptake in osteomedullary sites, OR patients are in ≥2nd CR/VGPR
  • Patients must be older than 1 year of age.
  • Prior treatment with murine and humanized 3F8 is allowed. Patients with prior m3F8, hu3F8, ch14.18 or hu14.18 treatment must have HAHA antibody titer ≤1300 Elisa units/ml. Human anti-mouse antibody positivity is allowed.
  • White blood cell count ≥1000/ul (phase I only)
  • Absolute neutrophil count ≥500/ul (phase I only)
  • Absolute lymphocyte count ≥500/ul (phase I only)
  • Platelet count ≥25,000/ul (phase I only)
  • No chemotherapy or immunotherapy for a minimum of three weeks prior to start of hu3F8
  • Women of child-bearing potential must be willing to practice an effective method of birth control while on treatment
  • Signed informed consent indicating awareness of the investigational nature of this program.

Exclusion Criteria:

  • Existing major organ dysfunction > grade 2, with the exception of hearing loss and hematologic toxicity (defined as suppression of all subtypes of WBCs, RBCs, and platelets).
  • Active life-threatening infection.
  • Pregnant women or women who are breast-feeding.
  • Inability to comply with protocol requirements, including PK studies and genetic studies (phase I only)
  • History of allergy to mouse proteins.
  • Human anti-hu3F8 antibody (HAHA) titer >1300 Elisa units/ml.
  • History of allergy to GM-CSF

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01757626

Contact: Brian Kushner, MD 212-639-6793
Contact: Shakeel Modak, MD 212-639-7623

United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Brian Kushner, MD    212-639-6793      
Contact: Shakeel Modak, MD    212-639-7623      
Principal Investigator: Brian Kushner, MD         
Sponsors and Collaborators
Memorial Sloan Kettering Cancer Center
Y-mAbs Therapeutics
Principal Investigator: Brian Kushner, MD Memorial Sloan Kettering Cancer Center

Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: Memorial Sloan Kettering Cancer Center Identifier: NCT01757626     History of Changes
Other Study ID Numbers: 12-230
First Posted: December 31, 2012    Key Record Dates
Last Update Posted: October 8, 2018
Last Verified: October 2018

Keywords provided by Memorial Sloan Kettering Cancer Center:
Bone Marrow

Additional relevant MeSH terms:
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Immunologic Factors
Physiological Effects of Drugs