Clinical Trials /

Ipilimumab and Nivolumab in Combination With Radiation Therapy in Treating Patients With Stage II-III Non-small Cell Lung Cancer

NCT04013542

Description:

This phase I trial studies the side effects of ipilimumab and nivolumab in combination with radiation therapy, and to see how well they work in treating patients with stage II-III non-small cell lung cancer. Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy rays to kill tumor cells and shrink tumors. Ipilimumab and nivolumab may also help radiation therapy work better by making tumor cells more sensitive to the radiation therapy. Giving ipilimumab and nivolumab in combination with radiation therapy may work better in treating patients with stage II-III non-small cell lung cancer compared to standard chemotherapy in combination with radiation therapy.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Ipilimumab and Nivolumab in Combination With Radiation Therapy in Treating Patients With Stage II-III Non-small Cell Lung Cancer
  • Official Title: A Pilot Trial of Ipilimumab-Nivolumab in Local-Regionally Advanced Non Small Cell Lung Cancer (NSCLC)

Clinical Trial IDs

  • ORG STUDY ID: 2018-0836
  • SECONDARY ID: NCI-2019-03205
  • SECONDARY ID: 2018-0836
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT04013542

Conditions

  • ALK Gene Rearrangement
  • EGFR Gene Mutation
  • Locally Advanced Lung Non-Small Cell Carcinoma
  • Lung Non-Small Cell Carcinoma
  • Stage II Lung Cancer AJCC v8
  • Stage IIA Lung Cancer AJCC v8
  • Stage IIB Lung Cancer AJCC v8
  • Stage III Lung Cancer AJCC v8
  • Stage IIIA Lung Cancer AJCC v8
  • Stage IIIB Lung Cancer AJCC v8
  • Stage IIIC Lung Cancer AJCC v8
  • Unresectable Lung Non-Small Cell Carcinoma

Interventions

DrugSynonymsArms
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyTreatment (nivolumab, ipilimumab, radiation therapy)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (nivolumab, ipilimumab, radiation therapy)

Purpose

This phase I trial studies the side effects of ipilimumab and nivolumab in combination with radiation therapy, and to see how well they work in treating patients with stage II-III non-small cell lung cancer. Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy rays to kill tumor cells and shrink tumors. Ipilimumab and nivolumab may also help radiation therapy work better by making tumor cells more sensitive to the radiation therapy. Giving ipilimumab and nivolumab in combination with radiation therapy may work better in treating patients with stage II-III non-small cell lung cancer compared to standard chemotherapy in combination with radiation therapy.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine safety and feasibility of ipilimumab-nivolumab (Bristol-Meyers-Squibb,
      Opdivo), a cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and programmed death 1 (PD-1)
      inhibitor in the treatment of local-regionally advanced non-small cell lung cancer (NSCLC).

      SECONDARY OBJECTIVES:

      I. To evaluate the clinical outcomes of treatment with ipilimumab-nivolumab concurrent with
      radiation therapy in patients with local-regionally advanced NSCLC.

      II. To observe and record anti-tumor activity. III. To identify potential predictive and
      prognostic biomarkers for early recurrence using circulating cell-free deoxyribonucleic acid
      (DNA) (cfDNA).

      IV. To identify potential predictive and prognostic biomarkers for early recurrence using
      tumor tissue PD-L1 immunohistochemistry (IHC).

      V. To identify potential predictive and prognostic biomarkers for early recurrence using
      tumor tissue tumor mutational burden (TMB).

      VI. To identify potential resistance mechanisms using immune biomarker and genetic analysis
      in post-progression biopsies.

      EXPLORATORY OBJECTIVES:

      I. Tumor tissue/blood biomarkers will be assessed for tumor mutation burden (TMB) and PD-L1
      immunohistochemistry.

      II. Patient microbiomes will be evaluated with stool specimen collection kits.

      OUTLINE:

      CONCURRENT THERAPY: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1
      and ipilimumab IV over 30 minutes on day 1. Treatment with nivolumab repeats every 21 days
      for up to 8 cycles, and treatment with ipilimumab repeats every 42 days for up to 4 cycles in
      the absence of disease progression or unacceptable toxicity. Within 1 day of starting
      nivolumab and ipilimumab, patients also undergo radiation therapy 5 days a week
      (Monday-Friday) over 6-7 weeks in the absence of disease progression or unacceptable
      toxicity.

      MAINTENANCE THERAPY: Patients then receive nivolumab IV over 30 minutes on day 1. Treatment
      repeats every 28 days for up to 8 cycles in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (nivolumab, ipilimumab, radiation therapy)ExperimentalCONCURRENT THERAPY: Patients receive nivolumab IV over 30 minutes on day 1 and ipilimumab IV over 30 minutes on day 1. Treatment with nivolumab repeats every 21 days for up to 8 cycles, and treatment with ipilimumab repeats every 42 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 1 day of starting nivolumab and ipilimumab, patients also undergo radiation therapy 5 days a week (Monday-Friday) over 6-7 weeks in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients then receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.
  • Ipilimumab
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically or cytologically confirmed NSCLC (any histology)

          -  Patients must have stage II or III local-regionally advanced NSCLC that is deemed to
             be best treated by systemic and concurrent radiotherapy. Eligible patients with stage
             II disease must be unresectable or refuse surgical resection

          -  No prior therapy for the current stage II or stage III NSCLC disease

          -  ECOG (Eastern Cooperative Oncology Group) performance status =< 2 (Karnofsky >= 60%)

          -  Leukocytes >= 2,000/mcL

          -  Absolute neutrophil count >= 1,000/mcL

          -  Platelets >= 75,000/mcL

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =<
             3 x institutional ULN

          -  Creatinine =< 1.5 x institutional ULN

          -  Glomerular filtration rate (GFR) >= 50 mL/min/1.73 m^2 for patients with creatinine
             levels above institutional normal

          -  No prior history of autoimmune disease, including but not limited to systemic lupus
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
             associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's
             syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune
             vasculitis, or glomerulonephritis

               -  Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid
                  replacement hormone may be eligible

               -  Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may
                  be eligible

               -  Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with
                  dermatologic manifestations only (e.g., patients with psoriatic arthritis would
                  be excluded) are permitted provided that they meet the following conditions:

                    -  Patients with psoriasis must have a baseline ophthalmologic exam to rule out
                       ocular manifestations

                    -  Rash must cover less than 10% of body surface area (BSA)

                    -  Disease is well controlled at baseline and only requiring low potency
                       topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%,
                       fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)

                    -  No acute exacerbations of underlying condition within the last 12 months
                       (not requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate,
                       retinoids, biologic agents, oral calcineurin inhibitors, high potency or
                       oral steroids)

          -  No prior history of idiopathic pulmonary fibrosis, pneumonitis (including drug
             induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
             pneumonia, etc.), or evidence of active pneumonitis on screening chest computerized
             tomography (CT) scan

          -  No active pregnancy. The effects of ipilimumab-nivolumab on the developing human fetus
             are unknown. For this reason and because radiation and possibly immunotherapies used
             in this trial are known or possibly known to be teratogenic, women of child-bearing
             potential and men must agree to use adequate contraception (hormonal or barrier method
             of birth control; abstinence) prior to study entry and for the duration of study
             participation. Should a woman become pregnant or suspect she is pregnant while she or
             her partner is 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 7
             months after completion of ipilimumab-nivolumab administration

          -  Ability to understand and the willingness to sign a written informed consent document

          -  Patients with known epidermal growth factor receptor (EGFR) mutation or anaplastic
             lymphoma kinase (ALK) rearrangement are eligible

        Exclusion Criteria:

          -  Prior systemic therapy for the current active local-regionally advanced NSCLC

          -  Patients who are receiving any other investigational agents

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to nivolumab

          -  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

          -  Pregnant women are excluded from this study because nivolumab is an immunotherapy
             agent with the potential for teratogenic or abortifacient effects. Because there is an
             unknown but potential risk for adverse events in nursing infants secondary to
             treatment of the mother with nivolumab, breastfeeding should be discontinued if the
             mother is treated with nivolumab. These potential risks may also apply to radiation
             therapy used in this study

          -  Known human immunodeficiency virus (HIV) positivity

          -  Active chronic treatment (that is still required) with systemic immunosuppressive
             medications (including but not limited to prednisone, cyclophosphamide, azathioprine,
             methotrexate, thalidomide, and anti-tumor necrosis factor [TNF] agents)

          -  Patients who have received acute, low dose, systemic immunosuppressant medications
             (e.g., a one-time dose of dexamethasone for nausea) may be enrolled. The use of
             inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients
             with orthostatic hypotension or adrenocortical insufficiency is allowed

          -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanized antibodies or fusion proteins

          -  Patients with prior allogeneic bone marrow transplantation or prior solid organ
             transplantation

          -  Active untreated hepatitis. Patients with known past or resolved hepatitis B infection
             (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive
             anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible. Patients
             positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain
             reaction (PCR) is negative for HCV RNA (ribonucleic acid). Hepatitis B virus (HBV) and
             HCV viral loads must also be undetectable

          -  Known active untreated tuberculosis

          -  Administration of a live, attenuated vaccine within 4 weeks before treatment start or
             anticipation that such a live attenuated vaccine will be required during the study.
             Influenza vaccination should be given during influenza season only (approximately
             October to March). Patients must not receive live, attenuated influenza vaccine (e.g.,
             FluMist) within 4 weeks prior to treatment start or at any time during the study

          -  Malignancies within 3 years prior to treatment start, with the exception of those with
             a negligible risk of metastasis or death and with expected curative outcome (such as
             adequately treated stage I-II cancers, carcinoma in situ of the cervix, basal or
             squamous cell skin cancer, localized prostate cancer treated surgically with curative
             intent, or ductal carcinoma in situ treated surgically with curative intent) or
             undergoing active surveillance per standard-of-care management (e.g., CLL [chronic
             lymphocytic leukemia] Rai stage 0, prostate cancer with Gleason score =< 6, and
             prostate-specific antigen [PSA] =< 10 mg/mL, etc.)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 2 years
Safety Issue:
Description:Safety and tolerability will be assessed by the incidence and severity of adverse events as determined by Common Terminology Criteria for Adverse Events version 5 and by physical examination findings, clinical laboratory tests, and vital signs, assessments.

Secondary Outcome Measures

Measure:Anti-tumor activity
Time Frame:Up to 2 years
Safety Issue:
Description:The anti-tumor activity of study treatment will be assessed by the site investigators according to the Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1).
Measure:Progression-free survival (PFS)
Time Frame:Up to 2 years
Safety Issue:
Description:Will be evaluated using the method of Kaplan-Meier. Confidence intervals around the median will be calculated using the Brookmeyer-Crowley method.
Measure:Overall survival (OS)
Time Frame:Up to 2 years
Safety Issue:
Description:Will be evaluated using the method of Kaplan-Meier. Confidence intervals around the median will be calculated using the Brookmeyer-Crowley method.
Measure:Time to local treatment failure
Time Frame:Up to 2 years
Safety Issue:
Description:Will be evaluated using the method of Kaplan-Meier. Confidence intervals around the median will be calculated using the Brookmeyer-Crowley method.
Measure:Time to distant treatment failure
Time Frame:Up to 2 years
Safety Issue:
Description:Will be evaluated using the method of Kaplan-Meier. Confidence intervals around the median will be calculated using the Brookmeyer-Crowley method.
Measure:Overall response rate
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Duration of response
Time Frame:Up to 2 years
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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