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Immunogenicity and Biomarker Analysis of Neoadjuvant Ipilimumab for Melanoma

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. Read our disclaimer for details. Identifier: NCT00972933
Recruitment Status : Completed
First Posted : September 9, 2009
Last Update Posted : December 7, 2017
Bristol-Myers Squibb
Information provided by (Responsible Party):
Diwakar Davar, University of Pittsburgh

Tracking Information
First Submitted Date  ICMJE September 3, 2009
First Posted Date  ICMJE September 9, 2009
Last Update Posted Date December 7, 2017
Study Start Date  ICMJE December 2009
Actual Primary Completion Date July 17, 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 8, 2009)
To study the effects of ipilimumab upon the host immune response in nodal metastatic melanoma and in the peripheral blood comparing pre-treatment with post-treatment (baseline, 6 weeks) immunologic features. [ Time Frame: 2.5 years ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 8, 2009)
  • To study the effects of ipilimumab upon the host immune response. [ Time Frame: 2.5 years ]
  • To collect pilot data comparing pre-treatment with post-treatment proteomic and genetic features. [ Time Frame: 2 years ]
  • To evaluate the clinical efficacy of preoperative neoadjuvant therapy with ipilimumab in high risk clinically and pathologically node-positive melanoma patients (AJCC stage IIIB-C). [ Time Frame: 5 years ]
  • To collect safety data and evaluate the safety of neoadjuvant therapy with ipilimumab in high risk clinically and pathologically node-positive melanoma patients (AJCC stage IIIB-C). [ Time Frame: 2.5 years ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Immunogenicity and Biomarker Analysis of Neoadjuvant Ipilimumab for Melanoma
Official Title  ICMJE Neoadjuvant Anti-CTLA4 Blockade With Ipilimumab in Patients With AJCC Stage IIIB-C (Tx,1-4, N1b,2b, 2c, 3, M0) Melanoma: Immunogenicity And Biomarker Analysis
Brief Summary

Ipilimumab is a manufactured monoclonal antibody, much like the antibodies usually made by the human body to fight off infection; however it is not known why the human body does not "fight off" a cancerous tumor. The idea behind developing this experimental drug is to stimulate the immune system to make antibodies to kill cancer cells. This research study is considered "experimental" because it has not received approval from the Food and Drug Administration (FDA) for the treatment of this type of cancer.

This monoclonal antibody has been specifically made to block Cytotoxic T Lymphocyte Antigen 4 (CTLA4), which is a protein found on cells of the immune system. CTLA4 seems to slow down the immune response, so blocking it with an anti-CTLA4 antibody may make the immune response more active. The purpose of this study is to see if Ipilimumab affects the response of the patient's immune system toward their cancer.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Melanoma
Intervention  ICMJE Drug: ipilimumab
Excisional Biopsy - baseline Induction ipilimumab 10 mg/kg IV day 0, 21 - baseline and week 3 Complete lymph node dissection - week ≥ 6 Maintenance Ipilimumab 10 mg/kg IV - Days 63 (+28 days) and, 84 (+28 days) - (3 weeks apart, starting 2-4 weeks following definitive lymphadenectomy)
Other Names:
  • MDX-010
  • Yervoy
  • BMS-734016
Study Arms  ICMJE Experimental: Ipilimumab
Induction ipilimumab 10 mg/kg IV day 0, 21 (baseline, week 3) Maintenance Ipilimumab 10 mg/kg IV days 63 (+28 days) and, 84 (+28 days) - (3 weeks apart, starting 2-4 weeks following definitive lymphadenectomy)
Intervention: Drug: ipilimumab
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 5, 2017)
Original Estimated Enrollment  ICMJE
 (submitted: September 8, 2009)
Actual Study Completion Date  ICMJE September 26, 2017
Actual Primary Completion Date July 17, 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Willing and able to give written informed consent.
  • Histologic diagnosis of melanoma belonging to T1-4 N1b,2b,2c,3 M 0 AJCC stages, that may present as any of the following groups:
  • Primary melanoma with clinically apparent (overt) regional lymph node metastases, confirmed by pathological diagnosis (biopsy).
  • Clinically detected recurrence of melanoma at the proximal regional lymph node(s) basin, confirmed by pathological diagnosis (biopsy).
  • Clinically or histologically detected primary melanoma involving multiple regional nodal groups, confirmed by pathological diagnosis (biopsy).
  • Clinically detected single site of nodal metastatic melanoma arising from an unknown primary, confirmed by pathological diagnosis (biopsy).
  • Patients are eligible for this trial either at presentation for primary melanoma with concurrent regional nodal metastasis, or at the time of clinically detected nodal recurrence. Patients must undergo biopsy (punch) or open biopsy (if done as part of a clinically indicated baseline diagnostic procedure) within 14 days of entry into the study. Lymphadenectomy will be performed after at least 2 and generally not longer than 4 weeks of ipilimumab therapy. Additional delays for definitive lymphadenectomy are allowed if clinically indicated while awaiting the resolution of potential adverse events from ipilimumab therapy.
  • Patients must have been evaluated by standard-of-care full body imaging studies (CT, PET-CT or MRI) as part of the initial clinical work-up at baseline (no more than 4 weeks prior to study enrollment) and after completion of 2 doses of ipilimumab (at 6-8 weeks after the first dose of ipilimumab and prior the definitive lymphadenectomy procedure).
  • Required values for initial laboratory tests:

    • White Blood Cell ≥ 3000/uL
    • Absolute Neutrophil Count ≥ 1500/uL
    • Platelets ≥ 100 x 103/uL
    • Hemoglobin ≥ 10 g/dL
    • Creatinine ≤ ULN
    • AST/ALT ≤ 2.5 x Upper Limit of Normal (ULN)
    • Bilirubin ≤ ULN, (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL)
    • PT/PTT ≤ ULN (No active or chronic infection with HIV, Hepatitis B, or Hepatitis C.)
  • Adequate performance status (ECOG 0, 1).
  • Men and women, ≥ 18 years of age.
  • Women of childbearing potential (WOCBP) must be willing to use an adequate method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the last dose of ipilimumab. WOCBP include any female who has experienced menarche and who has not undergone a successful surgical sterilization procedure (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not post-menopausal. Post-menopause is defined as:

    • Amenorrhea ≥ 12 consecutive months without another cause, or
    • For women with irregular menstrual periods and taking hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level ≥ 35 mIU/mL.
  • Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (eg, vasectomy) should be considered to be of childbearing potential. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours before the start of ipilimumab.

Exclusion Criteria:

  • Patients with clinical, radiological/laboratory, or pathological evidence of distant metastatic disease.
  • Patients with evidence of soft tissue involvement by gross extranodal extension of tumor manifest by fixation to the fascia, or matting of nodal tissue that would compromise surgical resection as determined by the surgical oncologist.
  • Patients who have had a history of acute diverticulitis, intra-abdominal abscess, GI obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation.
  • Any other malignancy from which the patient has been disease-free for less than 5 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix.
  • Autoimmune disease: Patients with a history of inflammatory bowel disease are excluded from this study, as are patients with a history of symptomatic disease (eg, rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [eg, Wegener's Granulomatosis]); motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome).
  • Any underlying medical or psychiatric condition, which in the opinion of the investigator will make the administration of ipilimumab hazardous or obscure the interpretation of AEs, such as a condition associated with frequent diarrhea.
  • Patients with underlying heart conditions who are deemed ineligible for surgery by cardiology consult.
  • Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1 month before or after any dose of ipilimumab).
  • A history of prior treatment with ipilimumab or prior CD137 agonist or CTLA-4 inhibitor or agonist.
  • A history of prior radiotherapy, chemotherapy, including infusion or perfusion therapy for his current disease or any immunotherapy including tumor vaccines, interferon-alfa, interleukins, levamisole or other biologic response modifiers within the past 4 weeks.
  • Concomitant therapy with any of the following: IL 2, interferon, or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids; unless discontinued ≥ 4 weeks.
  • Women of childbearing potential (WOCBP), defined above in Section 4.1, who:
  • are unwilling or unable to use an acceptable method of contraception to avoid pregnancy for their entire study period and for at least 8 weeks after cessation of study drug, or
  • have a positive pregnancy test at baseline, or
  • are pregnant or breastfeeding.
  • Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (eg, infectious) illness.

Before study enrollment, WOCBP must be advised of the importance of avoiding pregnancy during study participation and the potential risk factors for an unintentional pregnancy. All WOCBP MUST have a negative pregnancy test before first receiving ipilimumab. If the pregnancy test is positive, the patient must not receive ipilimumab and must not be enrolled in the study.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT00972933
Other Study ID Numbers  ICMJE 08-144
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Diwakar Davar, University of Pittsburgh
Study Sponsor  ICMJE Diwakar Davar
Collaborators  ICMJE Bristol-Myers Squibb
Investigators  ICMJE
Principal Investigator: Diwakar Davar, MD UPMC/UPCI
PRS Account University of Pittsburgh
Verification Date December 2017

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