Patient case: 57-year-old male with lung cancer; genetic feature: FGFR1

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

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.

Detailed description: Study Groups and Therapy:
  If you are found to be eligible to take part in this study, you will be assigned to a study part (to learn which dose level of nivolumab you will receive) and to 1 of 2 study arms (to learn which treatment combination you will receive). This is done because no one knows if one study part is the same, better, or worse than the other.
  -  If you are enrolled in Arm A, you will receive nivolumab by vein over about 1 hour every 2 weeks and radiation therapy.
  -  If you are enrolled in Arm B, you will receive ipilimumab by vein over about 90 minutes every 6 weeks, nivolumab by vein over about 1 hour every 2 weeks, and radiation therapy.
  The study doctor will decide which type of radiation therapy (either stereotactic radiosurgery [SRS] or whole brain radiation therapy [WBRT]) you will receive. If you receive SRS therapy, you will receive it 1 time. If you receive WBRT therapy, you will receive it 1 time each day for 10 days.
  If you are enrolled in Part 1 of the study, the dose of nivolumab you receive will depend on when you join this study. The first group of participants will receive the highest dose of nivolumab. If intolerable side effects are seen, the next group of participants will receive a lower dose.
  If you are enrolled in Part 2 of the study, the dose of nivolumab you receive will depend on the results seen in Part 1. The study doctor will tell you the dose of nivolumab you will receive.
  All participants will receive the same dose of ipilimumab and radiation therapy.
  Study Visits:
  Right before your first treatment and then over 2 weeks (+/- 3 days) after that:
  -  You will have a physical exam.
  -  Blood (about 1 tablespoon) will be drawn for routine tests.
  About 1 month after you have received radiation:
  -  You will have an MRI, CT, or PET/CT scan to check the status of the disease.
  -  You will complete the neurocognitive exam.
  Length of Study:
  You may continue to receive the study drug(s) unless the disease gets worse, if you have intolerable side effects, or if you are unable to follow study directions. You will only receive radiation therapy during the beginning of the study, either 1 time or for up to 10 days.
  If the disease appears to be getting worse or the tumors appear to be getting larger, you may still be able to receive the study drug if you and your doctor decide it is in your best interest. Sometimes the disease appears to get worse but the study drug is actually working.
  However, there are risks of continuing to receive the study drug(s) because the disease may actually be getting worse. You are still at risk for side effects due to the study drug(s). This could also delay starting other treatments. The disease may get worse to the point that you are no longer able to receive other treatments. The study doctor will discuss this option with you.
  Your participation on the study will be over after you have completed follow-up.
  Follow-Up:
  About 30 days after your last dose of study drug(s), you will have a physical exam.
  Long-Term Follow-Up:
  Every 12 weeks for up to 1 year:
  -  You will have a physical exam.
  -  Blood (about 1 tablespoon) will be drawn for routine tests.
  -  You will have an MRI, CT, or PET/CT scan to check the status of the disease.
  -  You will complete the neurocognitive exam.
  If the follow-up is done at another hospital, the information about your medical history, physical exam, routine blood tests, and imaging scans will be sent to MD Anderson for review. If you cannot come to MD Anderson for your follow up visits, the study team may call you every 12 weeks to ask how you are doing. Each call should last about 10 minutes.
  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.

Eligibility: 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 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
  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. 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.
  5. 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
  6. Has known carcinomatous meningitis (also known as leptomeningeal disease).
  7. Has an active infection requiring intravenous systemic therapy or hospital admission.
  8. 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.
  9. 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.
  10. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  11. 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.
  12. Has received a live vaccine 30 days prior to the first dose of trial treatment.
  13. Has experienced Grade 4 toxicity on treatment with prior radiation.
  14. 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.
  15. 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.
  16. Tumor exhibits epidermal growth factor receptor (EGFR) mutations or ALK re-arrangement that qualifies the patient for treatment with a systemic agent targeting these mutations.
  17. Allergies and adverse drug reaction to the following: History of allergy to study drug components; History of severe hypersensitivity reaction to any monoclonal antibody
  18. Previous CNS surgery within 2 weeks of treatment, with the exception of biopsy.
  19. Unable or unwilling to tolerate an intracranial MRI.
  20. In the first 5 patients enrolled in treatment groups on part B of this study (receiving combination ipilimumab and nivolumab), patients may have had 1-0 prior lines of systemic therapy after being diagnosed with metastatic disease. This restriction will be lifted in all subsequent cohorts of patients treated on part B.

Relevance to patient case: not relevant