Anti-LAG-3 Alone & in Combination w/ Nivolumab Treating Patients w/ Recurrent GBM (Anti-CD137 Arm Closed 10/16/18)
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ClinicalTrials.gov Identifier: NCT02658981 |
Recruitment Status :
Completed
First Posted : January 20, 2016
Last Update Posted : October 6, 2023
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Condition or disease | Intervention/treatment | Phase |
---|---|---|
Glioblastoma Gliosarcoma Recurrent Brain Neoplasm | Biological: Anti-LAG-3 Monoclonal Antibody BMS 986016 Biological: Anti-PD-1 Other: Pharmacological Study Other: Laboratory Biomarker Analysis Biological: Anti-CD137 | Phase 1 |
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 63 participants |
Allocation: | Non-Randomized |
Intervention Model: | Parallel Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | A Phase I Trial of Anti-LAG-3 or Anti-CD137 Alone and in Combination With Anti-PD-1 in Patients With Recurrent GBM |
Actual Study Start Date : | August 24, 2016 |
Actual Primary Completion Date : | April 30, 2022 |
Actual Study Completion Date : | October 3, 2023 |
Arm | Intervention/treatment |
---|---|
Experimental: A1 Anti-LAG-3
Patients receive Anti-LAG-3 monoclonal antibody BMS-986016 IV over 60 minutes and on days 1 and 15. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Pharmacological Study Laboratory Biomarker Analysis |
Biological: Anti-LAG-3 Monoclonal Antibody BMS 986016
Given IV Other: Pharmacological Study Correlative Studies Other: Laboratory Biomarker Analysis Correlative Studies |
Experimental: A2 Anti-CD137 (Urelumab)
Patients receive Anti-CD137 (Urelumab) IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 15 courses in the absence of disease progression or unacceptable toxicity Pharmacological Study Laboratory Biomarker Analysis |
Other: Laboratory Biomarker Analysis
Correlative Studies Biological: Anti-CD137 Given IV
Other Name: urelumab |
Experimental: B1 Anti-LAG3 + Anti-PD-1 (nivolumab)
Patients receive Anti-PD-1 (nivolumab) IV over 60 minutes and anti-LAG-3 monoclonal antibody BMS-986016 IV on days 1 and 15. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Pharmacological Study Laboratory Biomarker Analysis |
Biological: Anti-LAG-3 Monoclonal Antibody BMS 986016
Given IV Biological: Anti-PD-1 Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative Studies |
Experimental: B2 Anti-CD137 + Anti-PD-1
Patients receive Anti-PD-1 (nivolumab) IV over 60 minutes on days 1 and 15 and Anti-CD137 (urelumab) IV on day 1. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. (2pts enrolled before the Anti-CD137 antibody (BMS-663513 - urelumab) treatment arm closed by BMS on 10/16/18 due to closure of BMS Urelumab development program. Subjects currently on treatment may continue.) Pharmacological Study Laboratory Biomarker Analysis |
Biological: Anti-PD-1
Given IV
Other Names:
Other: Pharmacological Study Correlative Studies Other: Laboratory Biomarker Analysis Correlative Studies Biological: Anti-CD137 Given IV
Other Name: urelumab |
Experimental: Intratumoral Studies
Patients pre-operatively receive either anti-LAG-3 monoclonal antibody BMS-986016 (Arm A1), or urelumab (Arm A2), or nivolumab and anti-LAG-3 monoclonal antibody BMS-986016 as in Part B (B1)), or nivolumab and urelumab as in Part B (B2). Within 45 days of surgical resection, patients post-operatively receive drug from one of the four arms. (3pts enrolled before the Anti-CD137 antibody (BMS-663513 - urelumab) treatment arm closed by BMS on 10/16/18 due to closure of BMS Urelumab development program. Subjects currently on treatment may continue.) |
Biological: Anti-LAG-3 Monoclonal Antibody BMS 986016
Given IV Biological: Anti-PD-1 Given IV
Other Names:
Other: Pharmacological Study Correlative Studies Other: Laboratory Biomarker Analysis Correlative Studies Biological: Anti-CD137 Given IV
Other Name: urelumab |
- Maximum tolerated dose (MTD) of anti-LAG-3 monoclonal antibody BMS-986016 as monotherapy as determined by frequency of toxicity [ Time Frame: 4 weeks ]The frequency of toxicity will be tabulated by the tested dose or doses using descriptive statistics. The proportion of subjects who experienced grade 3 or above toxicities (as defined by CTCAE v. 5.0 [Common Terminology Criteria for Adverse Events]) will be estimated, along with 95% confidence interval. MTD will be confirmed as the maximum dose level at which ≤ 33% of participants experience a dose-limiting toxicity (DLT).
- Maximum tolerated dose (MTD) of anti-CD137 as monotherapy as determined by frequency of toxicity [ Time Frame: 4 weeks ]The frequency of toxicity will be tabulated by the tested dose or doses using descriptive statistics. The proportion of subjects who experienced grade 3 or above toxicities (as defined by CTCAE v. 5.0 [Common Terminology Criteria for Adverse Events]) will be estimated, along with 95% confidence interval. MTD will be confirmed as the maximum dose level at which ≤ 33% of participants experience a dose-limiting toxicity (DLT).
- MTD of Anti-LAG-3 + Anti-PD-1 as determined by frequency of toxicity [ Time Frame: 4 weeks ]The frequency of toxicity will be tabulated by the tested dose or doses using descriptive statistics. The proportion of subjects who experienced grade 3 or above toxicities (as defined by CTCAE v. 5.0 [Common Terminology Criteria for Adverse Events]) will be estimated, along with 95% confidence interval. MTD will be confirmed as the maximum dose level at which ≤ 33% of participants experience a dose-limiting toxicity (DLT).
- MTD of Anti-CD137 + Anti-PD-1 as determined by frequency of toxicity [ Time Frame: 4 weeks ]The frequency of toxicity will be tabulated by the tested dose or doses using descriptive statistics. The proportion of subjects who experienced grade 3 or above toxicities (as defined by CTCAE v. 5.0 [Common Terminology Criteria for Adverse Events]) will be estimated, along with 95% confidence interval. MTD will be confirmed as the maximum dose level at which ≤ 33% of participants experience a dose-limiting toxicity (DLT).
- Overall Survival [ Time Frame: 2 years or until time of death, whichever occurs first ]The Kaplan-Meier method will be used to estimate overall survival probability and median time of survival along with a 95% confidence interval.
- Progression-free survival rate [ Time Frame: 1 year ]To estimate PFS rate at one year, all patients with non-progressive disease and alive at one year will be evaluated by RANO and iRANO at one year to confirm non-progressive status. The proportion of patients who achieve PFS at one year will be estimated along with a 90% confidence interval, assuming underlying binomial distribution.
- Overall Response, assessed by RANO and iRANO [ Time Frame: up to 2 years ]To estimate an overall tumor response rate: the proportion of patients who have objective partial response or complete response during the course of treatment will be estimated, along with 95% confidence intervals using the exact binomial method regardless of dosage, single or combination treatment.
- Overall Response to anti-LAG-3 monoclonal antibody BMS-98601, assessed by RANO and iRANO [ Time Frame: up to 2 years ]The proportion of patients who have objective partial response or complete response to anti-LAG-3 monoclonal antibody BMS-98601 during the course of treatment will be estimated per dose level with 95% confidence interval.
- Overall Response to anti-CD137 as monotherapy, assessed by RANO and iRANO [ Time Frame: up to 2 years ]The proportion of patients who have objective partial response or complete response to anti-CD137 as monotherapy during the course of treatment will be estimated per dose level with 95% confidence interval.
- Overall Response to Anti-LAG-3 + Anti-PD-1, assessed by RANO and iRANO [ Time Frame: up to 2 years ]The proportion of patients who have objective partial response or complete response to Anti-LAG-3 + Anti-PD-1 combination therapy, during the course of treatment will be estimated per dose level with 95% confidence interval.
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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
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Patients must have histologically proven glioblastoma or gliosarcoma which is progressive or recurrent following radiation therapy and temozolomide
- Tumor O-6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) methylation status must be available; results of routinely used methods for MGMT methylation testing (e.g. mutagenically separated polymerase chain reaction [MSPCR] or quantitative polymerase chain reaction [PCR]) are acceptable
- Patients must have measurable contrast-enhancing disease (defined as at least 1 cm x 1 cm) by magnetic resonance imaging (MRI) imaging within 21 days of starting treatment (patients may have gross total resection, but should have measurable disease post-operatively); patients must be able to undergo MRI of the brain with gadolinium; patients must be maintained on a stable corticosteroid regimen (no increase for 5 days) prior to this baseline MRI
- Patients must be in first recurrence of glioblastoma following radiation therapy and temozolomide
- Patients must have recovered from severe toxicity of prior therapy; an interval of at least 12 weeks must have elapsed since the completion of radiation therapy or placement of Gliadel wafers, and at least 6 weeks must have elapsed from the last dose of temozolomide (TMZ); no prior therapies are allowed other than radiation, temozolomide, and Gliadel wafers (placed during the first surgery at diagnosis of GBM)
- Patients must have a Karnofsky performance status >= 60% (i.e. the patient must be able to care for himself/herself with occasional help from others)
- Absolute lymphocyte count >= 1000/ul
- Absolute neutrophil count >= 1,500/ul
- Platelets >= 100,000/ul
- Hemoglobin >= 9 g/dl
- Total bilirubin =< institutional upper limit of normal
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal
- Creatinine =< institutional upper limit of normal OR creatinine clearance >= 60 ml/min/1.73m^2 for patients with creatinine levels above institutional normal
- Activated partial thromboplastin time (APTT) or partial thromboplastin time (PTT) =< 1.5 x institutional upper limit of normal
- Patients must be able to provide written informed consent
- Women of childbearing potential must have a negative serum pregnancy test within 24 hours prior to treatment start; women of childbearing potential must agree to use two methods of contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study treatment, and through 23 weeks after the last dose of study drug; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and through 31 weeks after the last dose of study drug
- Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or bladder; patients with prior malignancies must be disease-free for >= five years
Exclusion Criteria:
-
Patients receiving any other investigational agents are ineligible
- Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to anti-LAG-3, anti-CD137, and anti-PD1 are ineligible; the investigator brochures can be referenced for more information
- Patients with active or recent history of known or suspected autoimmune disease are ineligible; subjects with type 1 diabetes mellitus, hypothyroidism only requiring hormone replacement, and skin disorders (vitiligo, psoriasis, or alopecia) not requiring systemic treatment, are permitted to enroll
- Patients with a condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of study entry are ineligible
- Patients must not be receiving greater than 1 mg dexamethasone/day (or an equivalent amount of an alternative corticosteroid) for at least 1 week prior to treatment start
- Patients must have no evidence of mass effect and no midline shift
-
Patients must have no evidence of significant hematologic, renal, or hepatic dysfunction; patients with underlying hepatocellular disease should be given careful risk/benefit consideration prior to enrollment; patients with a history of any chronic hepatitis as evidenced by the following are ineligible:
- Positive test for hepatitis B surface antigen (HBsAg)
- Positive test for qualitative hepatitis C viral load (by PCR) (Note: subjects with positive hepatitis C antibody and negative quantitative hepatitis C by PCR are eligible; history of resolved hepatitis A virus infection is not an exclusion criterion)
- History of alcoholic or non-alcoholic steatohepatitis (NASH), auto-immune hepatitis, or previous grade 3-4 drug-related hepatitis, or any form of chronic liver disease
- Patients must be hepatitis C virus (HCV) negative (by quantitative PCR [qPCR]) and hepatitis B virus core antibody (HBcAb) negative (no prior hepatitis B infection)
- Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, clinically significant cardiac disease, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, are ineligible
- Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with these agents
- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
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): NCT02658981
United States, Alabama | |
UAB Comprehensive Cancer Center | |
Birmingham, Alabama, United States, 35294-3410 | |
United States, California | |
Jonsson Comprehensive Cancer Center at UCLA | |
Los Angeles, California, United States, 90095 | |
United States, Maryland | |
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | |
Baltimore, Maryland, United States, 21231 | |
United States, Massachusetts | |
Massachusetts General Hospital Cancer Center | |
Boston, Massachusetts, United States, 02114 | |
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute | |
Boston, Massachusetts, United States, 02115 | |
United States, Michigan | |
Henry Ford Hospital | |
Detroit, Michigan, United States, 48202 | |
United States, New York | |
Memorial Sloan-Kettering Cancer Center | |
New York, New York, United States, 10021 | |
United States, North Carolina | |
Wake Forest University Comprehensive Cancer Center | |
Winston-Salem, North Carolina, United States, 27157-1096 | |
United States, Ohio | |
Cleveland Clinic Taussig Cancer Center | |
Cleveland, Ohio, United States, 44195 | |
United States, Pennsylvania | |
Abrams Cancer Center of the University of Pennsylvania | |
Philadelphia, Pennsylvania, United States, 19104 | |
Hillman Cancer Center at University of Pittsburgh Cancer Institute | |
Pittsburgh, Pennsylvania, United States, 15232 |
Study Chair: | Micheal Lim, MD | Johns Hopkins/ABTC |
Responsible Party: | Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins |
ClinicalTrials.gov Identifier: | NCT02658981 |
Other Study ID Numbers: |
ABTC 1501 IRB00095527 ( Other Identifier: JHM IRB ) UM1CA137443 ( U.S. NIH Grant/Contract ) |
First Posted: | January 20, 2016 Key Record Dates |
Last Update Posted: | October 6, 2023 |
Last Verified: | October 2023 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | No |
Glioblastoma Gliosarcoma Brain Neoplasms Recurrence Disease Attributes Pathologic Processes Astrocytoma Glioma Neoplasms, Neuroepithelial Neuroectodermal Tumors Neoplasms, Germ Cell and Embryonal Neoplasms by Histologic Type Neoplasms Neoplasms, Glandular and Epithelial Neoplasms, Nerve Tissue |
Central Nervous System Neoplasms Nervous System Neoplasms Neoplasms by Site Brain Diseases Central Nervous System Diseases Nervous System Diseases Nivolumab Relatlimab Antibodies Antibodies, Monoclonal Immunologic Factors Physiological Effects of Drugs Antineoplastic Agents, Immunological Antineoplastic Agents Immune Checkpoint Inhibitors |