Clinical Trials /

UCDCC#270: Avelumab and Stereotactic Ablative Radiotherapy in Non-responding and Progressing NSCLC Patients

NCT03158883

Description:

This is a pilot, single center, open-label study to examine the ORR, safety, and toxicity of avelumab in combination with SAR in non-responding and progressing NSCLC patients previously treated with a PD-1 Inhibitor.

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

Recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: UCDCC#270: Avelumab and Stereotactic Ablative Radiotherapy in Non-responding and Progressing NSCLC Patients
  • Official Title: UCDCC#270: A Pilot Study of Avelumab and Stereotactic Ablative Radiotherapy in Non-responding and Progressing NSCLC Patients Previously Treated With a PD-1 Inhibitor

Clinical Trial IDs

  • ORG STUDY ID: 1054028
  • SECONDARY ID: UCDCC#270
  • NCT ID: NCT03158883

Conditions

  • Metastatic Non-small Cell Lung Cancer (NSCLC)

Interventions

DrugSynonymsArms
Avelumabanti-PD-L1 IgG1 monoclonal antibodyNon-responders

Purpose

This is a pilot, single center, open-label study to examine the ORR, safety, and toxicity of avelumab in combination with SAR in non-responding and progressing NSCLC patients previously treated with a PD-1 Inhibitor.

Detailed Description

      Lung cancer is the leading cause of cancer deaths worldwide. More than half of lung cancer
      patients present with metastatic disease at diagnosis, with a median survival of only 10-12
      months. In recent years the development of more efficacious therapies for metastatic
      non-small cell lung cancer (NSCLC) based upon an improved understanding of the underlying
      tumor biology has resulted in an improvement in median overall survival by several months.
      However, survival remains poor for most patients and there remains an urgent unmet need for
      novel treatment strategies to improve survival for these patients.

      Avelumab is a fully human anti-PD-L1 IgG1 monoclonal antibody. In phase I studies, avelumab
      was well-tolerated at a dose of 10 mg/kg IV Q2 weeks with the most frequently observed
      treatment related adverse events including fatigue, infusion-related reactions, nausea,
      chills, diarrhea, and pyrexia. However, many patients will not respond to checkpoint
      inhibition, and developing strategies to further improve the efficacy and extend the benefit
      of these treatments to non-responding and progressing patients is an area of substantial
      need. Among NSCLC patients, approximately 80% of patients will not respond to a checkpoint
      inhibitor as monotherapy.

      Combinatorial strategies may increase response rates. Radiotherapy is an intriguing partner
      therapy, with preclinical and clinical studies confirming the immunomodulatory effects of
      radiotherapy. There is particularly interest in the use of radiotherapy in patients who have
      failed a checkpoint inhibitor as monotherapy as this approach will isolate the effects of
      radiation in enhancing response rates.

      Stereotactic ablative radiotherapy (SAR) (also known as stereotactic body radiotherapy or
      SBRT) has emerged as a potentially curative treatment option for patients with early stage,
      medically inoperable non-small cell lung cancer and as a safe and effective local treatment
      for metastatic lesions.

      The investigators hypothesize that local radiotherapy can augment the systemic effects of
      avelumab in NSCLC patients previously refractory to a checkpoint inhibitor previously used as
      standard-of-care treatment. This proposal seeks to gain insight into the clinical and
      biological efficacy of this combination.
    

Trial Arms

NameTypeDescriptionInterventions
Non-respondersExperimentalPatients who initially progress at first response assessment on a PD-1 inhibitor will be enrolled to the "non-responder" arm. Avelumab: 10 mg/kg administered by IV infusion q2w (1 cycle = 14 [±2] days). Stereotactic ablative radiotherapy (SAR): the prescription dose will be 50 Gy over 5 fractions of 10 Gy each on an every 2 day basis (i.e., 2-3 treatments per week, with a minimum of 40 hours and a maximum of 96 hours between treatments) and completed within 1.5-2 weeks. SAR treatment will not be repeated.
  • Avelumab
ProgressorsExperimentalPatients who initially present with PR, CR, or SD to a PD-1 inhibitor but subsequently progress will be enrolled to the "progressor" arm. Avelumab: 10 mg/kg administered by IV infusion q2w (1 cycle = 14 [±2] days). Stereotactic ablative radiotherapy (SAR): the prescription dose will be 50 Gy over 5 fractions of 10 Gy each on an every 2 day basis (i.e., 2-3 treatments per week, with a minimum of 40 hours and a maximum of 96 hours between treatments) and completed within 1.5-2 weeks. SAR treatment will not be repeated.
  • Avelumab

Eligibility Criteria

        Inclusion Criteria:

          1. Signed informed consent.

          2. Ability to comply with the protocol.

          3. Adults >18 years of age with histologically proven stage IV non-small cell lung
             cancer.

          4. At least two sites of measurable disease as defined by RECIST 1.1; one of which must
             be amenable to treatment with SAR and accessible for a mandatory pre-treatment biopsy
             and a post- treatment biopsy at physician discretion. If a pulmonary nodule is being
             considered for SAR it must range in size from 1-5 cm.

          5. Have provided written consent for protocol directed biopsies.

          6. Patients with treated supratentorial metastases are allowed if stable, the patient is
             off steroids or on a stable or decreasing dose of ≤10 mg daily prednisone (or
             equivalent) and no evidence of intracranial hemorrhage.

          7. Archival tumor sample available. A minimum of 10 unstained slides. No fine needle
             aspiration (FNAs) allowed or tumor tissue from bone.

          8. ECOG performance status score of 0 or 1 (Appendix 1).

          9. Life expectancy ≥ 3 months.

         10. Adequate hematologic and end organ function, defined by the following laboratory
             results obtained within 14 days of the first study treatment:

               1. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, and
                  hemoglobin ≥ 9 g/dL (may have been transfused)

               2. Liver function tests meeting the following criteria: total bilirubin level ≤ 1.5
                  × the upper limit of normal (ULN) range and AST and ALT levels ≤ 2.5 × ULN or AST
                  and ALT levels ≤ 5 × ULN (for subjects with documented metastatic disease to the
                  liver).

               3. INR and aPTT <1.5 × ULN (for patients on anticoagulation they must be receiving a
                  stable dose for at least 1 week prior to randomization)

               4. Creatinine clearance >30 mL/min by Cockcroft-Gault formula (or local
                  institutional standard method).

         11. No history of severe hypersensitivity reactions to other mAbs.

         12. No other active malignancy.

         13. No active autoimmune disease or a history of known or suspected autoimmune disease
             except as detailed in the exclusion criteria below.

         14. No chemotherapy or radiotherapy within the past 28 days.

         15. Any number of prior treatments is allowed. Must have failed at least one treatment
             regimen for metastatic disease and must have failed platinum-based chemotherapy
             (including as treatment for localized disease) or be deemed ineligible for
             platinum-based therapy by the treating medical oncologist.

         16. Most recent prior regimen was a PD-1 inhibitor (nivolumab or pembrolizumab) with
             progression. Last dose must have been delivered within 90 days of enrollment.

         17. Highly effective contraception for both male and female subjects if the risk of
             conception exists. (Note: The effects of the trial drug on the developing human fetus
             are unknown; thus, women of childbearing potential and men able to father a child must
             agree to use 2 highly effective contraception, defined as methods with a failure rate
             of less than 1% per year. Highly effective contraception is required at least 28 days
             prior, throughout and for at least 60 days after avelumab treatment.

         18. Negative serum pregnancy test at screening for women of childbearing potential.

        Exclusion Criteria:

          1. Patients whose tumors contain activating EGFR mutations or ALK rearrangement should be
             excluded from this study, unless disease has progressed on all available, approved
             therapies targeting the EGFR mutation or ALK rearrangement.

          2. All subjects with brain metastases, except those meeting the following criteria:

               1. Brain metastases that have been treated locally and are clinically stable for at
                  least 2 weeks prior to enrollment

               2. No ongoing neurological symptoms that are related to the brain localization of
                  the disease (sequelae that are a consequence of the treatment of the brain
                  metastases are acceptable)

               3. Subjects must be either off steroids or on a stable or decreasing dose of <10mg
                  daily prednisone (or equivalent)

          3. Leptomeningeal disease.

          4. Uncontrolled pleural or pericardial effusion or ascites that would require recurrent
             drainage.

          5. Uncontrolled tumor related pain.

          6. Uncontrolled hypercalcemia.

          7. Pregnant and lactating women.

          8. Uncontrolled concomitant disease.

          9. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular
             accident/stroke (<6 months prior to enrollment), myocardial infarction (<6 months
             prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart
             Association Classification Class II), or serious cardiac arrhythmia requiring
             medication

         10. Significant acute or chronic infections including, among others:

               1. Known history of testing positive test for human immunodeficiency virus (HIV) or
                  known acquired immunodeficiency syndrome (AIDS)

               2. Positive test for HBV surface antigen and / or confirmatory HCV RNA (if anti-HCV
                  antibody tested positive)

         11. Oral or IV antibiotics within 2 weeks prior to enrollment.

         12. Active tuberculosis

         13. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI CTCAE
             v 4.03), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more
             features of partially controlled asthma).

         14. Known hypersensitivity or allergy to any component of the avelumab formulation.

         15. Active autoimmune disease that might deteriorate when receiving an immunostimulatory
             agent:

               1. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease
                  not requiring immunosuppressive treatment are eligible

               2. Subjects requiring hormone replacement with corticosteroids are eligible if the
                  steroids are administered only for the purpose of hormonal replacement and at
                  doses ≤ 10 mg or 10 mg equivalent prednisone per day

               3. Administration of steroids through a route known to result in a minimal systemic
                  exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable

         16. Patients with a prior allogeneic bone marrow transplantation or prior solid organ
             transplantation.

         17. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced
             pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic
             organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan. A
             history of radiation pneumonitis in the radiation field (fibrosis) is permitted.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate
Time Frame:Up to 90 days after completion of study treatment
Safety Issue:
Description:Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria.

Secondary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 90 days after completion of study treatment.
Safety Issue:
Description:OS is defined as the duration of time from the start of treatment to death from any cause.
Measure:Progression-Free Survival (PFS)
Time Frame:From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 90 days after completion of study treatment.
Safety Issue:
Description:PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.
Measure:Disease Control Rate (DCR)
Time Frame:From date of randomization to end of study, assessed up to 90 days follow-up
Safety Issue:
Description:DCR is defined as the percentage of patients that achieve an objective tumor response or stable disease to therapy.
Measure:Duration of Stable Disease
Time Frame:From date of randomization to end of study, assessed up to 90 days follow-up
Safety Issue:
Description:SD is measured from the start of the treatment until the criteria for disease progression are met, taking as reference the smallest measurements recorded since the treatment started.
Measure:Duration of Overall Response
Time Frame:From date of randomization to end of study, assessed up to 90 days follow-up
Safety Issue:
Description:The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever status is recorded first) until the first date that recurrence or PD is objectively documented, taking as reference for PD the smallest measurements recorded since the treatment started.
Measure:Confirmation
Time Frame:From date of randomization to end of study, assessed up to 90 days follow-up
Safety Issue:
Description:The main goal of confirmation of objective response is to avoid overestimating the response rate observed. In cases where confirmation of response is not feasible, it should be made clear when reporting the outcome of such studies that the responses are not confirmed.
Measure:Immune Related Response Criteria
Time Frame:From date of randomization to end of study, assessed up to 90 days follow-up
Safety Issue:
Description:A growing body of literature indicates that radiographic responses to immunotherapy may have different patterns and kinetics than what would be expected with traditional cytotoxic therapies. To account for these differences we will also characterize radiographic outcomes using the immune related response criteria outlined by Wolchok and colleagues as an exploratory outcomes.
Measure:Evaluation of Best Overall Response
Time Frame:From date of randomization to end of study, assessed up to 90 days follow-up
Safety Issue:
Description:The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started). In general, the patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Megan Daly, MD

Trial Keywords

  • Avelumab
  • NSCLC
  • Stereotactic ablative radiotherapy (SAR)

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