Clinical Trials /

Concurrent or Sequential Immunotherapy and Radiation Therapy in Patients With Metastatic Lung Cancer

NCT03223155

Description:

Trial Design - Patients with stage IV non-small cell lung cancer are randomized to nivolumab/ipilimumab plus either sequential or concurrent stereotactic body radiotherapy (SBRT). - The primary endpoint is the phase I safety endpoint of SBRT dose for each body site. - The same starting SBRT dose levels are used in each arm. If two or more patients experience a dose-limiting toxicity (DLT) at the starting dose level, then the reduced dose level will be used (Section 7.1—Page 72). - DLT is defined as any grade ≥3 toxicity possibly, likely, or definitely related to SBRT plus nivolumab/ipilimumab (the combination and not the individual components). - Irradiated metastases will be grouped into one of five locations, which have different SBRT doses, and the DLTs will be attributed to the relevant organ system. - The starting and decreased SBRT dose levels are found in Table 2 (Page 20). - SBRT will be delivered in 3-5 fractions over the course of 1-1.5 weeks. - Patients in the sequential arm will begin immunotherapy between 1-7 days after completion of SBRT - Given the accrual data for IRB15-1130, the investigators anticipate that approximately 1/3 of patients will contribute metastasis to 2 locations. Since there are 2 arms, and 5 metastasis locations with 6 patients per location for the starting dose level, this translates to 40 patients for the starting dose level, and another 40 patients should each of the 5 locations require de-escalation to the lower dose level. - Secondary endpoints include comparisons of efficacy and toxicity between the arms, as well as interrogation of changes in the immune microenvironment induced by the two approaches.

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

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Concurrent or Sequential Immunotherapy and Radiation Therapy in Patients With Metastatic Lung Cancer
  • Official Title: A Randomized Phase I Trial to Evaluate Concurrent Or Sequential Ipilimumab, Nivolumab, and Stereotactic Body Radiotherapy in Patients With Stage IV Non-Small Cell Lung Cancer (COSINR Study)

Clinical Trial IDs

  • ORG STUDY ID: IRB17-0547
  • NCT ID: NCT03223155

Conditions

  • Stage IV Small Cell Lung Cancer

Interventions

DrugSynonymsArms
NivolumabOpdivoSequential Arm
IpilimumabYervoySequential Arm

Purpose

Trial Design - Patients with stage IV non-small cell lung cancer are randomized to nivolumab/ipilimumab plus either sequential or concurrent stereotactic body radiotherapy (SBRT). - The primary endpoint is the phase I safety endpoint of SBRT dose for each body site. - The same starting SBRT dose levels are used in each arm. If two or more patients experience a dose-limiting toxicity (DLT) at the starting dose level, then the reduced dose level will be used (Section 7.1—Page 72). - DLT is defined as any grade ≥3 toxicity possibly, likely, or definitely related to SBRT plus nivolumab/ipilimumab (the combination and not the individual components). - Irradiated metastases will be grouped into one of five locations, which have different SBRT doses, and the DLTs will be attributed to the relevant organ system. - The starting and decreased SBRT dose levels are found in Table 2 (Page 20). - SBRT will be delivered in 3-5 fractions over the course of 1-1.5 weeks. - Patients in the sequential arm will begin immunotherapy between 1-7 days after completion of SBRT - Given the accrual data for IRB15-1130, the investigators anticipate that approximately 1/3 of patients will contribute metastasis to 2 locations. Since there are 2 arms, and 5 metastasis locations with 6 patients per location for the starting dose level, this translates to 40 patients for the starting dose level, and another 40 patients should each of the 5 locations require de-escalation to the lower dose level. - Secondary endpoints include comparisons of efficacy and toxicity between the arms, as well as interrogation of changes in the immune microenvironment induced by the two approaches.

Trial Arms

NameTypeDescriptionInterventions
Sequential ArmExperimentalPatients will be randomized to either the Sequential Arm or the Concurrent Arm. Patients in the Sequential Arm will complete SBRT to 2-4 sites and then begin treatment with nivolumab/ipilimumab between 1-7 days after completion of SBRT.
  • Nivolumab
  • Ipilimumab
Concurrent ArmExperimentalPatients will be randomized to either the Sequential Arm or the Concurrent Arm. Patients in the Concurrent Arm will begin treatment with nivolumab/ipilimumab first and must complete planned SBRT to 2-4 sites within 2 weeks (prior to second dose of nivolumab).
  • Nivolumab
  • Ipilimumab

Eligibility Criteria

        Inclusion Criteria:

          -  1. Have a histologic diagnosis of stage IV NSCLC.

          -  2. Be willing and able to provide written informed consent/assent for the trial.

          -  3. Be greater than or equal to 18 years of age on day of signing informed consent.

          -  4. Have measurable disease based on RECIST 1.1 including at least two metastatic
             lesions that meet criteria for SBRT radiation.

             a. 0.25 cc to 65 cc of viable tumor (i.e. primary disease or metastases) approximately
             5cm in maximal dimension. Tumors larger than 65 cc can be partially treated

          -  5. For biopsy identified patients: Be willing to undergo repeat biopsy of a target
             lesion before treatment and after radiation. Subjects for whom newly-obtained samples
             cannot be provided (e.g. inaccessible or subject safety concern) may be exempted from
             this requirement after consultation with the Principal Investigator.

          -  6. Have a performance status of 0 or 1 on the ECOG Performance Scale.

          -  7. Demonstrate adequate organ function as defined in Table 1, all screening labs
             should be performed within 10 days of treatment initiation.

        Table 1 Adequate Organ Function Laboratory Values System Laboratory Value Hematological
        Absolute neutrophil count (ANC) ≥ 1,500 /mcL Platelets ≥ 100,000 / mcL Hemoglobin ≥ 9 g/dL
        or ≥ 5.6 mmol/L without transfusion or 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) ≤ 1.5 X upper limit of normal (ULN) OR ≥ 50 mL/min for
        subject with creatinine levels > 1.5 X institutional ULN

        Hepatic Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total
        bilirubin levels > 1.5 ULN AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects
        with liver metastases Albumin ≥ 3.0 mg/dL aCreatinine clearance should be calculated per
        institutional standard.

          -  8. Female subject of childbearing potential should have a negative urine or serum
             pregnancy within 24hours prior to receiving the first dose of study medication. If the
             urine test is positive or cannot be confirmed as negative, a serum pregnancy test will
             be required.

          -  9. 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 120 days 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.

          -  10. Male subjects should agree to use an adequate method of contraception starting
             with the first dose of study therapy through 120 days after the last dose of study
             therapy.

          -  11. Have an investigator determined life expectancy of at least 6 months.

          -  12. Patients whose tumors known to harbor an exon 19 deletion or exon 21 L858R EGFR
             mutation must have progressed on or had intolerance to an EGFR TKI. Patients whose
             tumors are known to harbor an ALK translocation must have progressed on or had
             intolerance to an ALK inhibitor.

        Exclusion Criteria:

          -  1. Has received prior chemotherapy for NSCLC with the exception of neoadjuvant or
             adjuvant platinum-based chemotherapy for NSCLC completed >6 months prior to
             enrollment.

          -  2. Has prior exposure to anti-PD1/PD-L1 or anti-CTLA4 therapy.

          -  3. Is currently participating and receiving study therapy or has participated in a
             study of an investigational agent and received study therapy or used an
             investigational device within 4 weeks of the first dose of treatment.

          -  4. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at a
             dose of >10mg prednisone daily or equivalent at time of first dose of trial treatment.

          -  5. Has a known history of active TB (Bacillus Tuberculosis).

          -  6. Hypersensitivity to nivolumab, ipilimumab, or any of its excipients.

          -  7. Has received radiation therapy within 2 weeks of study drug administration.

          -  8. 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.

          -  9. Patients with untreated symptomatic brain metastases. Patients with treated brain
             metastases will be allowed if brain imaging obtained greater than 7 days from
             treatment reveals stable disease. Patients with small (< 3mm) asymptomatic brain
             metastasis are allowed to enroll. Patients on steroids doses higher than 10 mg of
             prednisone (or its equivalent) are excluded.

          -  10. Has active autoimmune disease that has required systemic treatment in the past 2
             years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment.

          -  11. Has known history of non-infectious pneumonitis that required steroids or active
             pneumonitis.

          -  12. Has evidence of interstitial lung disease.

          -  13. Has an active infection requiring systemic therapy.

          -  14. Has a history or current evidence of any condition, therapy, or laboratory
             abnormality 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.

          -  15. Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

          -  16. Is pregnant or breastfeeding, or expecting to conceive or father children within
             the projected duration of the trial, starting with the screening visit through 120
             days after the last dose of trial treatment.

          -  17. If known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
             [qualitative] is detected) then patient is not eligible for cohorts including SBRT to
             liver lesions.

          -  18. 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.

          -  19. Has had prior radiation therapy (defined as >10% of prior prescription dose) to
             the area planning to be treated with SBRT.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of serious adverse events
Time Frame:Up to 4 years
Safety Issue:
Description:To determine the recommended SBRT dose to various metastatic locations in patients with stage IV NSCLC when delivered prior to or concurrently with nivolumab and ipilimumab.

Secondary Outcome Measures

Measure:Number of adverse events of grade 3-4 or higher
Time Frame:Up to 4 years
Safety Issue:
Description:To estimate and compare rates of ≥ grade 3-4 adverse events, by organ system, by CTCAEv4.0 that occur within 3 months from the start of SBRT when given prior to or concurrently with nivolumab/ipilimumab.
Measure:Rate of long term adverse events
Time Frame:Up to 4 years
Safety Issue:
Description:To estimate and compare the rates of long-term adverse events (after 3 months) from the end of SBRT when given prior to or concurrently with nivolumab/ ipilimumab.
Measure:Rate of response
Time Frame:From the start of treatment until the date of first documented progression or date of death from any cause, whichever comes first, up to 100 months
Safety Issue:
Description:Summarize and compare the response rate to determine the progression-free survival at 6 months with SBRT given either prior to or concurrently with nivolumab/ipilimumab.
Measure:Rate of lesion control
Time Frame:Up to 4 years
Safety Issue:
Description:To determine and compare the control of lesion(s) (SBRT treated and non-treated) when given either prior to or concurrently with nivolumab/ipilimumab.
Measure:Rate of change in tumor microenvironment
Time Frame:Up to 4 years
Safety Issue:
Description:To evaluate and compare changes in the tumor microenvironment induced by radiation when given prior to or concurrently with nivolumab/ipilimumab.
Measure:Rate of PD-L1 expression levels response
Time Frame:Up to 4 years
Safety Issue:
Description:To evaluate whether response to therapy correlates with PD-L1 expression levels among patients treated with nivolumab/ipilimumab either concurrently or sequential to SBRT.
Measure:Measure of peripheral blood cell T cell levels
Time Frame:From the start of treatment, not to exceed 4 years
Safety Issue:
Description:To explore whole PBMC by measuring peripheral blood cell T cell subset IFNγ ELISPOT levels throughout the study course and correlate with response to treatment.
Measure:Quantification of T cell receptor
Time Frame:From the start of treatment until the date of first documented progression or date of death from any cause, whichever comes first, up to 100 months
Safety Issue:
Description:To explore peripheral blood T cell receptor deep sequencing quantification of T cell receptor (TCR) repertoire changes throughout the study course and how TCR repertoire may correlate with progression free survival and/or overall survival.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Chicago

Trial Keywords

  • Small cell lung cancer
  • ipilimumab
  • nivolumab
  • stereotactic body radiotherapy

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