Nivo/Ipi Combination Therapy in Symptomatic Brain Metastases

NCT02621515 | Terminated Phase 2 DMC

• 1 other identifier: 201500776
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 4

Brief Summary

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.

Conditions

Melanoma; Brain Metastasis

Keywords

Nivolumab; Brain metastasis; Melanoma

Outcome Measures

Primary Outcomes (1)

• 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.

  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.

  2 years

Secondary Outcomes (7)

• The difference in BORR will be assessed between previously treated and previously untreated brain metastases using the RANO-BM criteria.

  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.

  2 years

• Duration of response (DOR)

  4 years

• Time to development of new brain metastases in responding patients

  4 years

• Progression free survival

  4 years

Study Arms (1)

Nivolumab

EXPERIMENTAL

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demonstrated, if unacceptable toxicity or intercurrent illness prevents further treatment, and when informed consent is withdrawn.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

Interventions

Nivolumab DRUG

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.

Also known as: Opdivo

Nivolumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects must be ≥18 years of age and competent to give informed consent.
• Histologically confirmed stage IV melanoma.
• 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.
• BRAF status is determined. If positive, initial treatment for maximal 8 weeks with BRAF-inhibitors is allowed.
• Subjects must be treatment-naive to nivolumab. (also as adjuvant treatment)
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
• 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

You may not qualify if:

• Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2 antibody. (also as adjuvant treatment)
• 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.
• 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.
• 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.)
• 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.
• Previous severe hypersensitivity reaction to treatment with another monoclonal antibody, or known hypersensitivity to study drugs components.
• A positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
• 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.
• A known psychiatric or substance abuse disorder that could interfere with cancer therapy.
• 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.
• Breastfeeding women.
• Inability to comply with other requirements of the protocol.

Sponsors & Collaborators

• University Medical Center Groningen: lead

Study Sites (4)

Dutch Cancer Institute/ A v. Leeuwenhoek Hospital

Amsterdam, 1066 CX, Netherlands

Location

VU Medical Center

Amsterdam, 1081 HZ, Netherlands

Location

University Medical Center Groningen

Groningen, 9713 GZ, Netherlands

Location

Erasmus Medical Center

Rotterdam, 3075 EA, Netherlands

Location

MeSH Terms

Conditions

Melanoma; Brain Neoplasms

Interventions

Nivolumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Geke AP Hospers, Md PhD

  University Medical Center Groningen

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 9, 2015
• First Posted: December 3, 2015
• Study Start: August 1, 2016
• Primary Completion: May 30, 2018
• Study Completion: May 30, 2018
• Last Updated: May 6, 2024

Record last verified: 2024-05

Locations

NL (4)