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

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ClinicalTrials.gov Identifier: NCT01757626
Recruitment Status : Recruiting
First Posted : December 31, 2012
Last Update Posted : May 1, 2020
Sponsor:
Collaborator:
Y-mAbs Therapeutics
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center

Tracking Information
First Submitted Date  ICMJE December 21, 2012
First Posted Date  ICMJE December 31, 2012
Last Update Posted Date May 1, 2020
Study Start Date  ICMJE December 2012
Estimated Primary Completion Date December 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 9, 2016)
  • 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.
  • 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
Original Primary Outcome Measures  ICMJE
 (submitted: December 21, 2012)
  • maximum tolerated dosage [ Time Frame: 1 year ]
    hu3F8 when combined with GM-CSF. DLT is defined after 1 cycle. Four dosage levels of hu3F8 will be tested with three to six patients at each dosage level.
  • 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
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 21, 2019)
  • 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 .
  • assess activity of hu3F8 plus GM-CSF against HR-NB [ Time Frame: 2 years ]
    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).
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 21, 2012)
  • pharmacokinetics of hu3F8 [ Time Frame: 1 year ]
    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 ~30 minutes pre- and ~5 mopntues post-infusion will also be measured for each dose of hu3F8 in cycles 2, 3 and 4.
  • 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).
  • 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Combination Therapy of Antibody Hu3F8 With Granulocyte- Macrophage Colony Stimulating Factor (GM-CSF) in Patients With Relapsed/Refractory High-Risk Neuroblastoma
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Neuroblastoma
Intervention  ICMJE
  • 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.
  • Biological: Hu3F8 With GM-CSF
    As determined by the phase I component of the study, the hu3F8 dosage in the phase II portion is 3 mg/kg/day. Patients who were treated in the phase I component are eligible for treatment in the phase II portion. Cycles are repeated approximately monthly through 5 cycles. Group 1 and Group 3 patients can continue to receive 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, whichever comes first. If HAHA becomes (+), cycles are deferred until it becomes (-) again. Patients who develop HAHA which precludes timely treatments with hu3F8+GM-CSF are eligible to receive low-dose maintenance regimens such as irinotecan alone,61 temozolomide alone,62 irinotecan-temozolomide,63 or cyclophosphamide-topotecan.64 They can also receive anti-HAHA agents such as rituximab and cyclophosphamide. They resume treatment with hu3F8+ GM-CSF if HAHA becomes negative. Patients may receive local radiation therapy.
Study Arms  ICMJE
  • 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 hu3F8+GM-CSF.in 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 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.
    Intervention: Biological: Hu3F8 With GM-CSF
  • Experimental: expansion phase II single arm trial
    Group 1 patients have primary refractory disease (no prior relapse but incomplete response to treatment) in BM as documented by histology and/or 123^I-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 123^I-MIBG scan. GM-CSF can be omitted if patients have a history of an allergy to GM-CSF or develop an allergic reaction to GM-CSF after initiating therapy while on the protocol.
    Intervention: Biological: Hu3F8 With GM-CSF
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 17, 2016)
224
Original Estimated Enrollment  ICMJE
 (submitted: December 21, 2012)
24
Estimated Study Completion Date  ICMJE December 2021
Estimated Primary Completion Date December 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 patients in ≥ 2nd CR patients are in ≥2nd CR
  • 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 a negative HAHA antibody titer. Human anti-mouse antibody (HAMA) 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.
  • Positive human anti-hu3F8 antibody (HAHA) titer
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Year and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Brian Kushner, MD 212-639-6793
Contact: Shakeel Modak, MD 212-639-7623
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01757626
Other Study ID Numbers  ICMJE 12-230
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Memorial Sloan Kettering Cancer Center
Study Sponsor  ICMJE Memorial Sloan Kettering Cancer Center
Collaborators  ICMJE Y-mAbs Therapeutics
Investigators  ICMJE
Principal Investigator: Brian Kushner, MD Memorial Sloan Kettering Cancer Center
PRS Account Memorial Sloan Kettering Cancer Center
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP