ClinicalTrials.gov
ClinicalTrials.gov Menu

Trial of Nivolumab With Radiation or Nivolumab and Ipilimumab With Radiation for the Treatment of Intracranial Metastases From Non-Small Cell Lung Cancer

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.
ClinicalTrials.gov Identifier: NCT02696993
Recruitment Status : Recruiting
First Posted : March 2, 2016
Last Update Posted : May 31, 2018
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:

There are 2 parts to this research study: Part 1 (dose escalation) and Part 2 (dose expansion).

The goal of Part 1 of this clinical research study is to find the highest tolerable dose of nivolumab that can be given either with radiation therapy alone or in combination with radiation and ipilimumab, in patients with NSCLC. The goal of Part 2 of this study is to learn if the dose of nivolumab found in Part 1 when given with radiation therapy and ipilimumab can help to control the disease.

This is an investigational study. Both WBRT and SRS radiation are FDA approved for local control of metastatic and primary tumors. Nivolumab is FDA approved and commercially available for the treatment of melanoma and NSCLC. Ipilimumab is FDA approved and commercially available for the treatment of melanoma. It is considered investigational to use radiation therapy, nivolumab, and ipilimumab to treat NSCLC. The study doctor can explain how the study drugs are designed to work.

Up to 80 participants will take part in this study. All will be enrolled at MD Anderson.


Condition or disease Intervention/treatment Phase
Metastatic Brain Cancer Drug: Nivolumab Drug: Ipilimumab Radiation: Stereotactic Radiosurgery (SRS) Radiation: Whole Brain Radiation Therapy (WBRT) Behavioral: Neurocognitive Exam Phase 1 Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Trial of Nivolumab With Radiation or Nivolumab and Ipilimumab With Radiation for the Treatment of Intracranial Metastases From Non-Small Cell Lung Cancer
Actual Study Start Date : December 2016
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Nivolumab + Stereotactic Radiosurgery (SRS)

Phase I: Nivolumab administered initially at 3 mg/kg by vein every 2 weeks. Stereotactic Radiosurgery (SRS) performed once, at dosage prescribed by treating physician. SRS performed optimally the day after the first administration of Nivolumab, but may occur within the first two weeks.

Neurocognitive exam completed at baseline and 1 month after radiation treatment.

Drug: Nivolumab

Phase I Starting Dose: 3 mg/kg by vein every 2 weeks.

Phase II Starting Dose: Maximum tolerated dose from Phase I, given by vein every two weeks.

Other Names:
  • BMS-936558
  • Opdivo

Radiation: Stereotactic Radiosurgery (SRS)

Phase I and Phase II:

Stereotactic Radiosurgery (SRS) performed once, at dosage prescribed by treating physician.


Behavioral: Neurocognitive Exam
Neurocognitive exam completed at baseline and 1 month after radiation treatment.

Experimental: Nivolumab + Whole Brain Radiation Therapy (WBRT)

Phase I: Nivolumab administered initially at 3 mg/kg by vein every 2 weeks. WBRT delivered to the whole brain 5 days a week. Participants treated to a total dose of 30 Gy in 10 fractions. WBRT performed optimally the day after the first administration of nivolumab, but may occur within the first two weeks.

Neurocognitive exam completed at baseline and 1 month after radiation treatment.

Drug: Nivolumab

Phase I Starting Dose: 3 mg/kg by vein every 2 weeks.

Phase II Starting Dose: Maximum tolerated dose from Phase I, given by vein every two weeks.

Other Names:
  • BMS-936558
  • Opdivo

Radiation: Whole Brain Radiation Therapy (WBRT)
Phase I and Phase II: Whole Brain Radiation Therapy (WBRT) delivered to the whole brain 5 days a week. Participants treated to a total dose of 30 Gy in 10 fractions.

Behavioral: Neurocognitive Exam
Neurocognitive exam completed at baseline and 1 month after radiation treatment.

Experimental: Nivolumab + Ipilimumab and Stereotactic Radiosurgery (SRS)

Phase II: Nivolumab administered by vein every two weeks at the maximum tolerated dose from Phase I. Ipilimumab 1 mg/kg by vein every 6 weeks. SRS performed optimally the day after the first administration of Ipilimumab , but may occur within the first two weeks.

Neurocognitive exam completed at baseline and 1 month after radiation treatment.

Drug: Nivolumab

Phase I Starting Dose: 3 mg/kg by vein every 2 weeks.

Phase II Starting Dose: Maximum tolerated dose from Phase I, given by vein every two weeks.

Other Names:
  • BMS-936558
  • Opdivo

Drug: Ipilimumab
Phase I and Phase II: Ipilimumab 1 mg/kg by vein every 6 weeks.
Other Names:
  • Yervoy
  • BMS-734016
  • MDX010

Radiation: Stereotactic Radiosurgery (SRS)

Phase I and Phase II:

Stereotactic Radiosurgery (SRS) performed once, at dosage prescribed by treating physician.


Behavioral: Neurocognitive Exam
Neurocognitive exam completed at baseline and 1 month after radiation treatment.

Experimental: Nivolumab+Ipilimumab and Whole Brain Radiation Therapy (WBRT)

Phase II: Nivolumab administered by vein every two weeks at the maximum tolerated dose from Phase I. Ipilimumab 1 mg/kg by vein every 6 weeks. WBRT delivered to the whole brain 5 days a week. Participants treated to a total dose of 30 Gy in 10 fractions. WBRT performed optimally the day after the first administration of nivolumab, but may occur within the first two weeks.

Neurocognitive exam completed at baseline and 1 month after radiation treatment.

Drug: Nivolumab

Phase I Starting Dose: 3 mg/kg by vein every 2 weeks.

Phase II Starting Dose: Maximum tolerated dose from Phase I, given by vein every two weeks.

Other Names:
  • BMS-936558
  • Opdivo

Radiation: Whole Brain Radiation Therapy (WBRT)
Phase I and Phase II: Whole Brain Radiation Therapy (WBRT) delivered to the whole brain 5 days a week. Participants treated to a total dose of 30 Gy in 10 fractions.

Behavioral: Neurocognitive Exam
Neurocognitive exam completed at baseline and 1 month after radiation treatment.




Primary Outcome Measures :
  1. Recommended Phase 2 Dose (RP2D) of Nivolumab in Combination with Stereotactic Radiosurgery (SRS) [ Time Frame: 6 weeks ]
    If acceptable toxicity is observed in first 10 patients, this dose considered the RP2D.

  2. Recommended Phase 2 Dose (RP2D) of Nivolumab in Combination with Whole Brain Radiation Therapy (WBRT) [ Time Frame: 8 weeks ]
    If acceptable toxicity is observed in first 10 patients, this dose considered the RP2

  3. Recommended Phase 2 Dose (RP2D) of Nivolumab in Combination with Ipilimumab and Stereotactic Radiosurgery (SRS) [ Time Frame: 6 weeks ]
    If acceptable toxicity is observed in first 10 patients, this dose considered the RP2

  4. Recommended Phase 2 Dose (RP2D) of Nivolumab in Combination with Ipilimumab and Whole Brain Radiation Therapy (WBRT) [ Time Frame: 8 weeks ]
    If acceptable toxicity is observed in first 10 patients, this dose considered the RP2


Secondary Outcome Measures :
  1. Intracranial Progression Free Survival [ Time Frame: 4 months ]
    Progression free survival assessed by MRI, CT, or PET/CT scan.

  2. Neurocognitive Changes [ Time Frame: Every 12 weeks for up to 1 year ]
    Neurocognitive changes assessed using the Hopkins Verbal Learning Revised (HVLT-R) total recall test.



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, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Pathologically confirmed non-small lung cancer.
  2. Stage IV metastatic disease with intracranial disease visible with magnetic resonance image (MRI).
  3. At least one brain lesion size >/=0.3 cm in the longest axis amenable to radiation therapy (either via SRS or WBRT)
  4. Be willing and able to provide written informed consent/assent for the trial.
  5. Be >/= 18 years of age on day of signing informed consent
  6. Have a performance status of 0 or 1 on the ECOG Performance Scale.
  7. Demonstrate adequate organ function as defined in the table below, all screening labs should be performed 28 days prior to study registration up to the first dose of study drug.
  8. Adequate Organ Function Laboratory Values: HEMATOLOGICAL=Absolute neutrophil count (ANC) >/=1,000 /mcL; Platelets >/= 100,000 /mcL; Hemoglobin >/= 9 g/dL or >/= 5.6 mmol/L. RENAL=Serum creatinine or Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) </=1.5 X upper limit of normal (ULN) or >/= 40 mL/min CrCl using the Cockcroft-Gault Formula. HEPATIC=Serum total bilirubin </= 1.5 X ULN (except for subjects with Gilbert Syndrome, who may have total bilirubin <3.0 mg/dl) or Direct bilirubin </=ULN for subjects with total bilirubin levels > 1.5 x ULN; aspartate aminotransferase (AST (SGOT)) and alanine aminotransferase (ALT (SGPT)) </= 3 X ULN or </= 5 X ULN for subjects with the liver metastases
  9. Inclusion #8 (continued): 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 Portional 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
  10. Female subject of childbearing potential should have a negative urine or serum pregnancy within 24 hours of study enrollment up to administration of the dose of study drug. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  11. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 31 weeks after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
  12. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 31 weeks after the last dose of study therapy.
  13. We will allow prior radiation to other sites, with no washout period, prior to study entry as long as the high dose regions of the prior and proposed radiation fields do not overlap. In patients where the prior high dose area would overlap with the high dose area of the intended radiation, a 4 month washout period will be required. The safety of such treatment will be at discretion of the treating radiation oncologist.
  14. Prior CNS radiation is allowed as long as cumulative radiation doses do not exceed tolerance of critical structures as judged by the treating radiation oncologist.

Exclusion Criteria:

  1. Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment or 5 half-lives, whichever is shorter.
  2. Has a diagnosis of severe active scleroderma, lupus, other rheumatologic or autoimmune disease within the past 3 months. Patients with a documented history of clinically severe autoimmune disease or a syndrome requiring systemic steroids or immunosuppressive agents will not be allowed on this study. Subjects with vitiligo or resolved childhood asthma/atopy are an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections are not excluded from the study. Subjects with hypothyroidism stable on hormone replacement are not excluded from this study.
  3. Has had a prior monoclonal antibody within 4 weeks or 5 half-lives, whichever is shorter, prior to study Day 1 or who has not recovered (i.e., </= Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
  4. For the Nivolumab only arm patients who received anti PD1 or anti PD-L1 therapies will be excluded, for Ipilimumab and Nivolumab arms patients who received anti PD1 or anti PD L1 therapies will be eligible
  5. Has had prior chemotherapy or targeted small molecule therapy within 3 weeks prior to administration of the study drug or who has not recovered (i.e., </= Grade 1 or at baseline) from adverse events due to a previously administered agent. *Note: Subjects with permanent </= Grade 2 toxicities (e.g. neuropathy) or toxicities corrected through routine medical management (e.g. thyroid replacement for hypothyroidism), are an exception to this criterion and may qualify for the study. *Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. *Note: Subjects with </= Grade 2 amylase or lipase elevations abnormalities that have no corresponding clinical manifestations (e.g. manifestation of pancreatitis), are an exception to this criterion and may qualify for the study.
  6. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, indolent lymphomas, or in situ cervical cancer that has undergone potentially curative therapy
  7. Has known carcinomatous meningitis (also known as leptomeningeal disease).
  8. Has an active infection requiring intravenous systemic therapy or hospital admission.
  9. Has a history or current evidence of any condition, therapy, or laboratory abnormality, including psychiatric or substance abuse disorder, that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
  10. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 31 weeks after the last dose of trial treatment.
  11. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  12. 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.
  13. Has received a live vaccine 30 days prior to the first dose of trial treatment.
  14. Has experienced Grade 4 toxicity on treatment with prior radiation.
  15. Has experienced Grade 3-4 intracranial toxicity (hypophysitis or CNS toxicity) with either prior intracranial radiation, anti programmed cell death-1 (PD-1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor therapy.
  16. Is taking > 4mg/day of dexamethasone or its equivalent at the start of immunotherapy or has required > 4mg/day of dexamethasone or its equivalent for 3 consecutive days within 1 week of starting treatment.
  17. Patients whose tumor exhibit activating EGFR mutation, ALK or ROS translocation and have a standard of care molecular targeted therapy available for these mutations, will be excluded from this study. Patients who progressed or could not tolerate these standard of care molecular targeted agents are eligible for this study. Adenocarcinoma patients may be consented prior to the EGFR and ALK status being known, but EGFR and ALK status must be determined prior to initiating therapyTumor
  18. Allergies and adverse drug reaction to the following: History of allergy to study drug components; History of severe hypersensitivity reaction to any monoclonal antibody
  19. Previous CNS surgery within 2 weeks of treatment, with the exception of biopsy.
  20. Unable or unwilling to tolerate an intracranial MRI.

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): NCT02696993


Contacts
Contact: Jing Li, MD 713-563-2300

Locations
United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Bristol-Myers Squibb
Investigators
Principal Investigator: Jing Li, MD M.D. Anderson Cancer Center

Additional Information:
Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT02696993     History of Changes
Other Study ID Numbers: 2015-0883
NCI-2016-00661 ( Registry Identifier: NCI CTRP )
First Posted: March 2, 2016    Key Record Dates
Last Update Posted: May 31, 2018
Last Verified: May 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M.D. Anderson Cancer Center:
Metastatic Brain Cancer
Non-small cell lung cancer with brain metastasis
NSCLC
Intracranial disease
Stereotactic radiosurgery
SRS
Whole brain radiation therapy
WBRT
Neurocognitive exam
Nivolumab
BMS-936558
Opdivo
Ipilimumab
Yervoy
BMS-734016
MDX010

Additional relevant MeSH terms:
Brain Neoplasms
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Neoplasm Metastasis
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Neoplastic Processes
Pathologic Processes
Central Nervous System Neoplasms
Nervous System Neoplasms
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Nivolumab
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs