Ipilimumab and Nivolumab in Leptomeningeal Metastases

Phase II Trial of Ipilimumab and Nivolumab in Leptomeningeal Metastases

This research study is studying a combination of two drugs as a possible treatment for Leptomeningeal Metastases.

The names of the study interventions involved in this study are:

• Ipilimumab
• Nivolumab

Study Overview

• Status: Completed
• Conditions: Leptomeningeal Carcinomatosis
• Intervention / Treatment: Drug: Nivolumab; Drug: Ipilimumab

Detailed Description

This research study is a Phase II clinical trial.

Researchers hope to study the effects of the combination of Nivolumab and Ipilimumab. Many cancers use specific pathways, such as programmed death-1 (PD-1), programmed death-ligand-1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4), to evade the body's immune system. Nivolumab and ipilimumab work by blocking the PD-1/PD-L1 and CTLA-4 pathways and thus releasing the brakes on the immune system so it can stop or slow cancer.

The FDA (the U.S. Food and Drug Administration) has approved Nivolumab and Ipilimumab as a treatment option for melanoma, but has not approved them for use when cancer cells spread to the cerebrospinal fluid

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Dana Farber Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participants must have histologically or cytologically confirmed disease from any solid tumor
• Age ≥18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (Karnofsky ≥60%)
• Life expectancy of greater than 3 weeks
• Participants must have normal organ and marrow function as defined below, all screening labs should be performed within 10 days of treatment initiation.

Adequate Organ Function Laboratory Values:

Unit key: mcL = microliter, ULN = upper limit normal

• Hematological

  • Absolute neutrophil count (ANC) ≥1500 /mcL
  • Platelets ≥100,000 / mcL
  • Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or Erythropoietin (EPO) dependency (within 7 days of assessment)
• Renal

• Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤ Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below):

  • Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL
  • Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL

• Hepatic

  • Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
  • Aspartate transaminase (AST) and Alanine transaminase (ALT) ≤ 3 ULN OR ≤ 5 X ULN for subjects with liver metastases
  • Albumin ≥ 2.5 mg/dL

• Coagulation

  • International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
  • Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
  • Creatinine clearance should be calculated per institutional standard.
• Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for Nivolumab to undergo five half-lives) after the last dose of investigational drug.
• 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
• Women must not be breastfeeding
• 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 investigational product. Women who are not of childbearing potential, ie, who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception
• Ability to understand and the willingness to sign a written informed consent document.
• Stable dose of dexamethasone 2 mg or less for 7 days prior to initiation of treatment
• Carcinomatous meningitis, as defined by positive cytology

Exclusion Criteria:

• Participants who have had chemotherapy, targeted small molecule therapy or study therapy within 14 days of protocol treatment, or those who have not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 2 weeks earlier. Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Participants who are receiving any other investigational agents.
• Patients should be excluded if they have 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
• Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 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. Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if > 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
• As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab combinations, drugs with a predisposition to hepatoxicity should be used with caution in patients treated with nivolumab-containing regimen.
• Patients should be excluded if they have had prior systemic treatment with an anti-CTLA4 antibody
• Has a known history of active TB (Bacillus Tuberculosis)
• Patients should be excluded if they are positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
• Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). These participants are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
• Has known history of, or any evidence of active, non-infectious pneumonitis.
• Has an active infection requiring systemic therapy.
• Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
• History of allergy to study drug components
• History of severe hypersensitivity reaction to any monoclonal antibody

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Combination Of Nivolumab with Ipilimumab; All patients will be treated based on their primary tumor diagnosis with a combination regimen of Nivolumab and Ipilimumab. Each treatment cycle is 6 weeks; exceptions below.; Melanoma:Nivolumab 1 mg/kg and Ipilimumab 3 mg/kg, every 3 weeks for 4 doses.Followed by Nivolumab 480 mg every 4 weeks until disease progression. Each cycle of monotherapy is defined as 8 weeks.; Non-small Cell Lung Cancer / Head and Neck Cancer:- Nivolumab 3 mg/kg every 2 weeks, and Ipilimumab 1 mg/kg every 6 weeks.; Small Cell Lung Cancer / Breast Cancer / Bladder Cancer:Nivolumab 1 mg/kg and Ipilimumab 3 mg/kg, every 3 weeks for 4 doses.Followed by Nivolumab 240 mg every 2 weeks until disease progression.; Renal Cell Carcinoma / Other Solid Tumors (not listed above):Nivolumab 3 mg/kg and Ipilimumab 3 mg/kg, every 3 weeks for 4 doses.Followed by Nivolumab 480 mg every 4 weeks until disease progression. Each cycle of monotherapy is defined as 8 weeks.

Drug: Nivolumab; Melanoma:- Combination therapy with Nivolumab 1 mg/kg for 4 doses followed by monotherapy Nivolumab 480 mg per cycle.; Non-small Cell Lung Cancer / Head and Neck Cancer:- Combination therapy with Nivolumab 3 mg/kg; Small Cell Lung Cancer / Breast Cancer / Bladder Cancer:- Combination therapy with Nivolumab 1 mg/kg for 4 doses followed by monotherapy Nivolumab 240 mg per cycle.; Renal Cell Carcinoma / Other Solid Tumors (not listed above):Combination therapy with Nivolumab 3 mg/kg for 4 doses followed by monotherapy Nivolumab 480 mg per cycle.; Other Names: Opdivo; Drug: Ipilimumab; Non-small Cell Lung Cancer / Head and Neck Cancer:- Combination therapy with Ipilimumab 1 mg/kg; Small Cell Lung Cancer / Breast Cancer / Bladder Cancer:- Combination therapy with Ipilimumab 3 mg/kg for 4 doses; Renal Cell Carcinoma / Other Solid Tumors (not listed above):Combination therapy with Ipilimumab 3 mg/kg for 4 doses; Other Names: Yervoy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Overall Survival	Overall Survival (OS) is defined as the time from registration to death due to any cause, or censored at date last known alive.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Treatment-related Adverse Events	Grade 3 or 4 treatment-related adverse events occurring in at least 15% of participants, based on CTCAE v4.0 criteria.	2 years
Cumulative Incidence of Progressive Disease at 3 Months for Intracranial Sites	Cumulative incidence describes the average probability of developing progressive disease (PD) by immunotherapy response assessment for neuro-oncology (iRANO) criteria. PD is defined as any of the following: (1) >/= 25% increase in 2-dimensional contrast lesions; (2) significant worsened changes on T2-weighted MRI scans; (3) new lesion; or (4) significant clinical decline. Confirmation of progressive disease is based on follow-up imaging for participants without significant clinical decline.	3 months post-treatment
Cumulative Incidence of Progressive Disease at 3 Months for Extracranial Sites	Cumulative incidence describes the average probability of developing progressive disease (PD) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. PD is defined as any of the following: (1) >/= 25% increase in 2-dimensional contrast lesions; (2) significant worsened changes on T2-weighted MRI scans; (3) new lesion; or (4) significant clinical decline. Confirmation of progressive disease is based on follow-up imaging for participants without significant clinical decline.	3 months post-treatment
Number of Participants With Leptomeningeal Disease (LMD) Response Post-Treatment	Cerebrospinal fluid (CSF) collection and cytology is done 6-9 weeks after treatment initiation to assess for LMD response, especially complete response or partial response. Complete Response is defined as: Reversion to negative CSF cytology (or NA); Disappearance of all disease related symptoms present prior to therapy (or NA); Complete disappearance of all detectable radiographic evidence of disease (or NA). Partial Response is defined as: > 50% decrease in malignant CSF cytology; Improvement in neurologic symptoms or no worsening of symptoms; Improvement in radiographic evidence of disease. No new sites of measurable or assessable central nervous system (CNS) disease.	6-9 weeks after treatment initiation
Extracranial Progression-Free Survival	Extracranial Progression-Free Survival (EPFS) is defined as the time from first dose of study drug to documented extracranial disease progression or death, whichever occurs first. Extracranial disease progression is assessed with CT scans of the chest, abdomen, and pelvis, by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria and immune-related response criteria (irRC) criteria. Progression is defined using RECIST v1.0 as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The follow-up of participants who have neither died nor progressed at the time of analysis will be censored at the date of last adequate disease assessment.	2 years
Intracranial Progression-Free Survival	Intracranial Progression-Free Survival (IPFS) is defined as the time from first dose of study drug to documented intracranial disease progression or death, whichever occurs first. Intracranial disease progression is assessed with CT or MRI scans of the brain, using the Response assessment in neuro-oncology (RANO) criteria, which defines progression as: ≥ 25% increase in in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline; or; Presence of new lesions; or; Worsening of clinical/neurologic status (unless clearly unrelated to the cancer); or; Worsening of non-measurable disease. The follow-up of participants who have neither died nor progressed at the time of analysis will be censored at the date of last adequate disease assessment.	2 years

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: Bristol-Myers Squibb

Publications and helpful links

General Publications

• Brastianos PK, Strickland MR, Lee EQ, Wang N, Cohen JV, Chukwueke U, Forst DA, Eichler A, Overmoyer B, Lin NU, Chen WY, Bardia A, Juric D, Dagogo-Jack I, White MD, Dietrich J, Nayyar N, Kim AE, Alvarez-Breckenridge C, Mahar M, Mora JL, Nahed BV, Jones PS, Shih HA, Gerstner ER, Giobbie-Hurder A, Carter SL, Oh K, Cahill DP, Sullivan RJ. Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis. Nat Commun. 2021 Oct 12;12(1):5954. doi: 10.1038/s41467-021-25859-y.

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 15, 2018
• Primary Completion (ACTUAL): July 22, 2021
• Study Completion (ACTUAL): July 22, 2021

Study Registration Dates

• First Submitted: August 29, 2016
• First Submitted That Met QC Criteria: October 18, 2016
• First Posted (ESTIMATE): October 20, 2016

Study Record Updates

• Last Update Posted (ACTUAL): November 14, 2022
• Last Update Submitted That Met QC Criteria: October 21, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Leptomeningeal Metastases
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Neoplastic Processes; Central Nervous System Neoplasms; Nervous System Neoplasms; Meningeal Neoplasms; Carcinoma; Neoplasm Metastasis; Meningeal Carcinomatosis; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab; Ipilimumab
• Other Study ID Numbers: 16-136

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No