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Nivo/Ipi Combination Therapy in Symptomatic Brain Metastases (CA209-322)

This study is currently recruiting participants.
Verified May 2017 by G.A.P. Hospers, University Medical Center Groningen
Sponsor:
ClinicalTrials.gov Identifier:
NCT02621515
First Posted: December 3, 2015
Last Update Posted: May 9, 2017
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.
Information provided by (Responsible Party):
G.A.P. Hospers, University Medical Center Groningen
  Purpose
The effect of nivolumab on symptomatic brain metastases is currently unknown. This phase 2 clinical trial will be the first to evaluate this intracranial effect in humans, with the aim to give these patients the possibility to be treated with anti-PD-1. Besides the objective response rate, long term benefits in this patient category will be evaluated by measuring survival in terms of progression free survival and overall survival. Furthermore safety and tolerability of administration of this drug in patients with symptomatic brain metastases will be studied, as this is the first study for nivolumab in this specific patient category.

Condition Intervention Phase
Melanoma Brain Metastasis Drug: Nivolumab Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: An Open-label, Single-arm, Phase II, Multicenter Study to Evaluate the Efficacy of Nivolumab/Ipilimumab Combination Therapy in Metastatic Melanoma Patients With Symptomatic Brain Metastases.

Resource links provided by NLM:


Further study details as provided by G.A.P. Hospers, University Medical Center Groningen:

Primary Outcome Measures:
  • The best overall response rate (BORR) of brain metastases to nivolumab will be assessed on Magnetic Resonance Imaging (MRI) using the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. [ Time Frame: 2 years ]
    Per patient, the BORR of brain metastases to nivolumab will be assessed in terms of complete response, partial response, stable disease and progressive disease. An MRI of the brain will be used for radiologic response evaluation. Response evaluation will be performed according to the RANO-BM criteria.


Secondary Outcome Measures:
  • The difference in BORR will be assessed between previously treated and previously untreated brain metastases using the RANO-BM criteria. [ Time Frame: 2 years ]
  • The difference in BORR will be assessed between intracranial metastases on and extra-cranial metastases within the same patient, using the RANO-BM criteria and the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria respectively. [ Time Frame: 2 years ]
    Evaluation of intracranial metastases will be performed using MRI. Evaluation of extracranial metastases will be performed using CT.

  • Duration of response (DOR) [ Time Frame: 4 years ]
    DOR is defined as the time between the date of first documented response (CR or PR) to the date of the first documented progression as determined by the RANO-BM criteria, or death due to any cause, whichever occurs first.

  • Time to development of new brain metastases in responding patients [ Time Frame: 4 years ]
    For all responding patients, the time between response to study treatment, as assessed on MRI using the RANO-BM criteria, occurence of new brain metastases will be measured.

  • Progression free survival [ Time Frame: 4 years ]
    Progression free survival is defined as the time from first administration of nivolumab to the date of the first documented progression, as determined by the RANO-BM criteria, or death due to any cause, whichever occurs first.

  • Overall survival [ Time Frame: 4 years ]
    Overall survival is defined as the time between the date of first administration of nivolumab and the date of death.

  • The number of patients with treatment related adverse events as assessed by CTCAE v4.0. [ Time Frame: 4 years ]

Estimated Enrollment: 70
Study Start Date: August 2016
Estimated Study Completion Date: January 2018
Estimated Primary Completion Date: January 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Nivolumab
All patients in this trial will receive treatment with nivolumab for 24 months. Treatment will be discontinued if confirmed disease progression has been demonstrated, if unacceptable toxicity or intercurrent illness prevents further treatment, and when informed consent is withdrawn. After discontinuation of treatment, follow-up will start. Duration of follow-up depends on survival of patients, with a maximum of 24 months. Therefore the end of this study is determined as 24 months after the last patient in this trial has started follow-up, has died, withdraws consent or is lost to follow-up for a different reason
Drug: Nivolumab
All patients in this phase 2 trial will receive treatment with nivolumab, a monoclonal antibody against the PD1-receptor on T cells. Dosing will be based on patients' weight (3 mg/kg). It will be administered in an intravenous infusion every 2 weeks and for a maximum of 2 years.
Other Name: Opdivo

Detailed Description:

This study is an open label, single arm, phase II clinical trial of prospectively collected data evaluating efficacy and safety of nivolumab in metastatic melanoma patients with symptomatic brain metastases. It will be conducted in several study centers in the Netherlands.

Patients with radiologic evidence of brain metastases and who are eligible for treatment with nivolumab will be screened for inclusion.

All patients in this trial will receive treatment with nivolumab for 24 months. Treatment will be discontinued if confirmed disease progression has been demonstrated, if unacceptable toxicity or intercurrent illness prevents further treatment, and when informed consent is withdrawn. After discontinuation of treatment, follow-up will start. Duration of follow-up depends on survival of patients, with a maximum of 24 months. Therefore the end of this study is determined as 24 months after the last patient in this trial has started follow-up, has died, withdraws consent or is lost to follow-up for a different reason.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Subjects must sign informed consent prior to inclusion in this trial.
  2. Subjects must be ≥18 years of age and competent to give informed consent.
  3. Histologically confirmed stage IV melanoma.
  4. At least one radiologic new lesion in the brain by MRI, which should be measurable by RANO-BM criteria (longest diameter ≥ 10 mm and perpendicular diameter ≥ 5 mm). Lesions with prior local treatment (i.e., SRT or surgical resection) can be considered measurable if there has been demonstrated progression since the time of local treatment. Leptomeningeal involvement is allowed, but could not be used as target lesion.
  5. BRAF status is determined. If positive, initial treatment for maximal 8 weeks with BRAF-inhibitors is allowed.
  6. Subjects must be treatment-naive to nivolumab. (also as adjuvant treatment)
  7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
  8. Subjects must have adequate organ function as defined by the following laboratory values (determined within 28 days prior to randomization/registration):

    • White blood cells (WBC) ≥ 2000 /µL
    • Absolute neutrophil count (ANC) ≥ 1500 /µL
    • Platelets ≥ 100 x103 /µL
    • Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L
    • Serum creatinine ≤ 1.5 times upper limit of normal (ULN) or creatinine clearance > 40 ml/min (using the Cockcroft-Gault formula)
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 times ULN
    • Bilirubin ≤ 1.5 times ULN (Except patient with Gilbert Syndrome, who can have total bilirubin ≤ 3.0 mg/dL)
    • LDH < 2 times ULN
  9. Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 24 hours prior to receiving the first administration of nivolumab. Women with non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥ 1 year.
  10. Women of child-bearing potential (WOCBP) and men who are sexually active with WOCBP must agree to use appropriate method(s) of contraception. (see section 5.2)

Exclusion Criteria:

  1. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2 antibody. (also as adjuvant treatment)
  2. Subjects who have not recovered to Common Terminology Criteria for Adverse Events (CTCAE) v4.0 grade 1 or better from adverse events due to previous cancer therapy.
  3. Evidence for an active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
  4. Treatment with corticosteroids in an increasing dosage in the 7 days prior to the first administration of nivolumab. (A stable or decreasing dosage of ≤ 4 mg dexamethasone or equivalent is allowed. In addition, inhaled or topical steroids and adrenal replacement doses are permitted in the absence of active autoimmune disease.)
  5. Previous malignancies (except non-melanoma skin cancers, in situ bladder cancer, gastric or colon cancers, cervical cancers/dysplasia or breast carcinoma in situ) unless a complete remission was achieved at least 1 years prior to study entry and no additional therapy is required or anticipated to be required during the study period.
  6. Previous severe hypersensitivity reaction to treatment with another monoclonal antibody, or known hypersensitivity to study drugs components.
  7. A positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
  8. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
  9. Any serious or uncontrolled medical disorder or active infection that, in the opinion of the investigator, may increase the risk associated with study participation, study drug administration, or would impair the ability of the patients to receive protocol therapy.
  10. A known psychiatric or substance abuse disorder that could interfere with cancer therapy.
  11. Women of childbearing potential with a positive serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab.
  12. Breastfeeding women.
  13. Inability to comply with other requirements of the protocol.
  Contacts and Locations
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 ClinicalTrials.gov identifier (NCT number): NCT02621515


Contacts
Contact: Geke Hospers, MD PhD 0503616161 g.a.p.hospers@umcg.nl
Contact: Geke Hospers, MD PhD 05036161 g.a.p.hospers@umcg.nl

Locations
Netherlands
Dutch Cancer Institute/ A v. Leeuwenhoek Hospital Not yet recruiting
Amsterdam, Netherlands, 1066 CX
Contact: Christian U. Blank, MD, PhD    +31205122570    c.blank@nki.nl   
VU Medical Center Not yet recruiting
Amsterdam, Netherlands, 1081 HZ
Contact: Alfonsus JM van den Eertwegh, MD, PhD    +31204444336    vandeneertwegh@vumc.nl   
University Medical Center Groningen Recruiting
Groningen, Netherlands, 9713 GZ
Contact: G.A. P. Hospers, MD, PhD    +31 50 3612821    g.a.p.hospers@umcg.nl   
Erasmus Medical Center Not yet recruiting
Rotterdam, Netherlands, 3075 EA
Contact: Wim HJ Kruit, MD, PhD    +31107041754    w.kruit@erasmusmc.nl   
Sponsors and Collaborators
University Medical Center Groningen
Investigators
Principal Investigator: Geke AP Hospers, Md PhD University Medical Center Groningen
  More Information

Responsible Party: G.A.P. Hospers, Principal investigator, University Medical Center Groningen
ClinicalTrials.gov Identifier: NCT02621515     History of Changes
Other Study ID Numbers: 201500776
First Submitted: September 9, 2015
First Posted: December 3, 2015
Last Update Posted: May 9, 2017
Last Verified: May 2017

Keywords provided by G.A.P. Hospers, University Medical Center Groningen:
Nivolumab
Brain metastasis
Melanoma

Additional relevant MeSH terms:
Nivolumab
Melanoma
Neoplasm Metastasis
Neoplasms, Second Primary
Brain Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Neoplastic Processes
Pathologic Processes
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs