Combining Radiosurgery and Nivolumab in the Treatment of Brain Metastases

Melanoma Clinical Trial

Official title:

A Phase II, Multi-centre Study, of Combining Radiosurgery and Nivolumab in the Treatment of Brain Metastases From Non-small Cell Lung Cancer and Renal Cell Cancer

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02978404
• Other study ID #: 16.206
• Secondary ID: OZM-080
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: June 2, 2017
• Est. completion date: December 31, 2023

Study information

• Verified date: February 2023
• Source: Centre hospitalier de l'Université de Montréal (CHUM)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Stereotactic radiosurgery (SRS) is increasingly administered as the sole treatment of brain metastases, in order to spare acute and long term side effects associated with whole brain radiotherapy. Local control of SRS treated lesions is good, but patients tend to develop additional brain metastases subsequently.

Nivolumab is a modulator of the immune system. Treatment with Nivolumab is associated with an increase in local control and survival in patients with non-small cell lung cancer and clear cell renal cell carcinoma. In the presence of Nivolumab, treatment of brain metastases with SRS may trigger an immune reaction against cancer. Therefore, the combination of SRS with Nivolumab may reduce the development of new brain metastases and improve patient survival.

The purpose of this study is to assess the effect of combining Nivolumab and SRS in controlling cancer progression. SRS will be administered to patients while they are receiving Nivolumab.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 26
• Est. completion date: December 31, 2023
• Est. primary completion date: January 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Men and women, = 18 years of age

2. Willing and able to give written informed consent

3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 within 28 days prior to registration

4. Radiation Therapy Oncology Group (RTOG) neurological function score of 0-1 within 28 days prior to registration

5. Histologic diagnosis of NSCLC, SCLC, Melanoma OR ccRCC

6. Stage IV cancer with brain metastases (Patients may have untreated primary disease)

7. Presenting with previously un-irradiated brain metastasis (10 cc maximum volume of brain disease based on the diagnostic screening MRI done within 28 days of registration))

8. Measurable/evaluable brain disease

9. Having received less than 4 lines of prior systemic treatments

10. Ability to be treated with either gamma knife or a linear accelerator based radiosurgery system

11. Ability to complete neurocognitive exams without assistance

12. Ability to complete QOL questionnaires with or without assistance

13. Screening laboratory values must meet the following criteria and should be obtained within 28 days prior to registration:

• White Blood Cell (WBC) = 2000/uL

• Absolute Neutrophil Count (ANC) = 1.5 x 109/L

• Platelets= 100 x 109/L

• Hemoglobin = 90 g/L (may be transfused)

• Serum creatinine = 1.5 x Upper Limit of Normal (ULN) or Creatinine Clearance = 50 ml/min (calculated -cockcroft-Gault)

• Aspartate aminotransferase/alanine aminotransferase (AST/ALT) =3 x ULN without liver metastasis,= 5 x ULN with liver metastases

• Total Bilirubin = 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)

14. Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (28 days plus the time required for Nivolumab to undergo five half-lives) after the last dose of investigational drug

15. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of Nivolumab

16. Women must not be breastfeeding

17. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving Nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of Nivolumab product. Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception).

Exclusion Criteria:

1. Brain metastasis in the brainstem

2. Patients who experienced prior seizures are eligible, however patients should not have had a seizure within 7 days of registration without the use of corticosteroids.

3. All other cancer histology other than NSCLC or ccRCC

4. Patients who cannot undergo MRI

5. 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

6. Patients with a condition requiring systemic treatment with either corticosteroids including steroids used for treating peritumoral edema (> 50 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.

7. Drugs with a predisposition to hepatoxicity should be used with caution in patients treated with Nivolumab-containing regimen

8. Any underlying medical or psychiatric condition, which in the opinion of the investigator will make the administration of Nivolumab hazardous or obscure the interpretation of AEs, such as a condition associated with frequent diarrhea.

9. History of prior treatment with a CTLA-4, PD-1 or PD-L1 inhibitor, CD137 agonist, or anti-PD-L2.

10. Concomitant therapy with any of the following: IL-2, interferon, or other non-study immunotherapy regimens; immunosuppressive agents; other investigation therapies

11. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (eg, infectious) illness.

12. Known history of hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection

13. History of allergy to study drug components.

14. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).

Related Conditions & MeSH terms

• Brain Metastases, Adult
• Brain Neoplasms
• Carcinoma, Non-Small-Cell Lung
• Carcinoma, Renal Cell
• Clear-Cell Metastatic Renal Cell Carcinoma
• Lung Neoplasms
• Melanoma
• Neoplasm Metastasis
• Non Small Cell Lung Cancer Metastatic
• Small Cell Lung Cancer
• Small Cell Lung Carcinoma

Intervention

Drug:
• Nivolumab
Nivolumab is administered to patients to a maximum of 2 year.

Radiation:
• Radiosurgery
Up to 10 cubic centimeter of brain metastases will be treated with radiosurgery. The dose of radiosurgery depends on the size of individual metastases.

Locations

Country	Name	City	State
Canada	Centre Hospitalier de l'Université de Montréal	Montreal	Quebec
Canada	McGill University Health Centre	Montreal	Quebec
Canada	Jewish General Hospital	Montréal	Quebec
Canada	Centre Hospitalier Universitaire de Sherbrooke	Sherbrooke	Quebec

Sponsors (2)

Lead Sponsor	Collaborator
Centre hospitalier de l'Université de Montréal (CHUM)	Bristol-Myers Squibb

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Intracranial progression-free survival	To evaluate whether the combination SRS with Nivolumab will improve the intracranial progression-free survival of patients.; Response will be assessed as per RECIST version 1.1.	1 year
Secondary	Treated brain lesions control rate	Treated brain lesions control will be assessed as per RECIST version 1.1.	1 year
Secondary	Overall survival after receiving Nivolumab.	Overall Survival is assessed at the end of the study at 2 years. A subject will be classified as either alive or dead due to any cause.; The time to event will be calculated as the time from Day 1 until date of death.; Day 1 is the date of 1st treatment consisting of an infusion of Nivolumab.	2 years
Secondary	Maximum response rate of distant non-irradiated disease	Response will be assessed as per RECIST version 1.1.	1 year
Secondary	Progression-free survival	Response will be assessed as per RECIST version 1.1.	1 year
Secondary	Correlation between tumor PD-L1 expression and clinical outcomes	Tumor PD-L1 expression level will be correlated with patient overall response rate, loco-regional recurrence free survival and overall survival.	1 year
Secondary	Patient quality of life	Quality of life will be assessed using the the Functional Assessment of Cancer Therapy - General (FACT-G) and the Brain Subscale (FACT-BR) questionnaires. A composite score will be obtained from the score of each subscale. Quality of life decline is the time to the first minimal important difference in the composite score from baseline.	1 year
Secondary	Neurocognitive function, as measured by the HVLT-R	Neurocognitive function will be assessed using the Hopkins Verbal Learning Test - Revised (HVLT-R). Neurocognitive failure is the time to the first failure on the assessments using the Reliable Change Index. Baseline neurocognitive function will be compared to the test results at 1 year using either a t-test or Wilcoxon-Mann-Whitney test, depending on the normality of the data.	1 Year
Secondary	Neurocognitive function, as measured by TMT	Neurocognitive function will be assessed using the Trail Making Test (TMT). Neurocognitive failure is the time to the first failure on the assessments using the Reliable Change Index. Baseline neurocognitive function will be compared to the test results at 1 year using either a t-test or Wilcoxon-Mann-Whitney test, depending on the normality of the data.	1 year
Secondary	Neurocognitive function, as measured by COWA	Neurocognitive function will be assessed using the Controlled Oral Word Association (COWA). Neurocognitive failure is the time to the first failure on the assessments using the Reliable Change Index. Baseline neurocognitive function will be compared to the test results at 1 year using either a t-test or Wilcoxon-Mann-Whitney test, depending on the normality of the data.	1 Year
Secondary	Acute and late toxicity of SRS + Nivolumab	Adverse events will be coded according to MedDRA. The results will be tabulated to examine their frequency, organ systems affected, severity, and relationship to study treatment.; Terminology Criteria for Adverse Events (CTCAE) V4.03 will be used for grading of AEs. Investigators will provide their assessment of causality as 1) unrelated, 2) unlikely, 3) possibly related, 4) probably, or 5) definitely related.	1 year
Secondary	Imaging indicators of response	Patient response to the treatment will be analysed using the Immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) criteria.	1 year