Clinical Trials /

Atezolizumab and Varlilumab in Combination With Radiation Therapy for NSCLC

NCT04081688

Description:

This phase I trial studies the side effects of atezolizumab, varlilumab, and radiation therapy in treating patients with non-small cell lung cancer that has spread to other places in the body (advanced) and cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies such as atezolizumab may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Immunotherapy with monoclonal antibodies such as varlilumab may induce changes in body?s immune system and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving atezolizumab, varlilumab, and radiation therapy may increase the amount of time the disease is not active or does not spread to another part of the body.

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

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Atezolizumab and Varlilumab in Combination With Radiation Therapy for NSCLC
  • Official Title: A Phase I Trial of Atezolizumab and Varlilumab in Combination With Radiation in Patients With Metastatic Non-Small Cell Lung Cancer (NSCLC)

Clinical Trial IDs

  • ORG STUDY ID: 031912
  • SECONDARY ID: NCI-2019-05810
  • SECONDARY ID: Pro2019000923
  • SECONDARY ID: 031912
  • SECONDARY ID: P30CA072720
  • NCT ID: NCT04081688

Conditions

  • Metastatic Lung Non-Small Cell Carcinoma
  • Refractory Lung Non-Small Cell Carcinoma
  • Stage III Lung Cancer AJCC v8
  • Stage IIIA Lung Cancer AJCC v8
  • Stage IIIB Lung Cancer AJCC v8
  • Stage IIIC Lung Cancer AJCC v8
  • Stage IV Lung Cancer AJCC v8
  • Unresectable Lung Non-Small Cell Carcinoma

Interventions

DrugSynonymsArms
Atezolizumab 1200 MG in 20 ML InjectionATEZOLIZUMAB, MPDL 3280A, MPDL 328OA, MPDL-3280A, MPDL3280A, MPDL328OA, RG7446, RO5541267, TecentriqTreatment (varlilumab, atezolizumab, SBRT)
Varlilumab 3 mg/kgCDX 1127, CDX-1127, Immunoglobulin G1, Anti-(Human CD Antigen CD27) (Human Monoclonal CDX-1127 Clone 1f5 Heavy Chain), Disulfide with Human Monoclonal CDX-1127 Clone 1f5 Kappa-chain, Dimer, VARLILUMABTreatment (varlilumab, atezolizumab, SBRT)

Purpose

This phase I trial studies the side effects of atezolizumab, varlilumab, and radiation therapy in treating patients with non-small cell lung cancer that has spread to other places in the body (advanced) and cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies such as atezolizumab may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Immunotherapy with monoclonal antibodies such as varlilumab may induce changes in body?s immune system and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving atezolizumab, varlilumab, and radiation therapy may increase the amount of time the disease is not active or does not spread to another part of the body.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To assess the safety and tolerability of combined therapy with atezolizumab and varlilumab
      in combination with radiation in adult patients with metastatic non-small cell lung cancer
      (NSCLC) who have progressed on prior PD-1/PD-L1 therapy.

      SECONDARY OBJECTIVES:

      I. To determine objective response rate (excluding the irradiated lesion) of therapy with
      atezolizumab and varlilumab in combination with radiation.

      II. To estimate clinical benefit rate of the combination. III. To estimate median
      progression-free survival of the combination. IV. To compare the frequency of immune-related
      adverse events (irAEs).

      OUTLINE:

      Patients receive varlilumab intravenously (IV) over 90 minutes on day 1 and atezolizumab IV
      over 30-60 minutes on day 2. Cycles repeat every 21 days for up to 1 year (18 cycles) in the
      absence of disease progression or unacceptable toxicity. Beginning on day 8 of cycle 1,
      patients also receive 4 or 5 fractions of stereotactic body radiation therapy (SBRT) over
      15-30 minutes every 2 days over 1.5-2 weeks.

      After completion of study treatment, patients are followed up at 30 days, then every 3 months
      for up to 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (varlilumab, atezolizumab, SBRT)ExperimentalPatients receive varlilumab IV over 90 minutes on day 1 and atezolizumab IV over 30-60 minutes on day 2. Cycles repeat every 21 days for up to 1 year (18 cycles) in the absence of disease progression or unacceptable toxicity. Beginning on day 8 of cycle 1, patients also receive 4 or 5 fractions of SBRT over 15-30 minutes every 2 days over 1.5-2 weeks.
  • Atezolizumab 1200 MG in 20 ML Injection
  • Varlilumab 3 mg/kg

Eligibility Criteria

        Inclusion Criteria:

          -  Must have signed and dated written informed consent form in accordance with regulatory
             and institutional guidelines

          -  Histological or cytological evidence of advanced, unresectable NSCLC

          -  Patients must be PD-1/PD-L1 experienced with disease progression documented either on
             therapy with anti-PD-1/PD-L1 or within 12 weeks of the last dose. Treatment should be
             initiated at least 4 weeks since last dose of PD-1/PD-L1 targeted therapy

          -  Patients must have progressed on at least one line of prior platinum-based
             chemotherapy in the metastatic setting. Subjects with unresectable stage III NSCLC who
             received platinum-based chemotherapy as part of chemoradiation or consolidation
             chemotherapy after chemoradiation are eligible if they progress within 6 months of
             last dose of chemotherapy. Treatment should be initiated at least 4 weeks since last
             dose of systemic therapy

          -  Subjects with an actionable molecular alteration (such as EGFR mutation, ALK or ROS1
             rearrangement, BRAF V600E mutation) are eligible only after failing standard-of-care
             targeted therapy with tyrosine kinase inhibitor (TKI). Patients with a EGFR T790M
             resistant mutation must have failed a 3rd generation TKI such as osimertinib

          -  Must not have received any prior therapy with immune regulatory molecule (such as
             targeting OX-40, IDO-1, LAG-3) or anti-CD27 monoclonal antibody (including varlilumab)

          -  Must have at least one lesion that has not previously been irradiated (and is not
             within a previously radiated field) and for which palliative radiation is potentially
             indicated. The lesion to be irradiated must be in the lung. Patient must have at least
             one additional measurable lesion (other than the lesion being radiated) as per
             immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) criteria.
             Patient must agree to undergo a mandatory biopsy of the non-irradiated lesion
             pre-treatment and post-treatment (after cycle 2). Pre-treatment tissue obtained by
             biopsy or resection performed according to standard of care may be utilized, provided
             tissue was obtained within 8 weeks of study entry, and subsequent to the last systemic
             anticancer therapy received

          -  Patients should have fewer than 10 metastatic sites and expected survival of more than
             3 months

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          -  Treatment to be initiated at least 2 weeks since last dose of prior systemic
             anticancer therapy (chemotherapy, radiation, and/or surgery)

          -  Recovery to grade 1 of any clinically significant toxicity (excluding alopecia, grade
             2 fatigue, vitiligo, endocrinopathies on stable replacement therapy, grade 2
             neuropathy from chemotherapy and grade 2 hearing loss from platinum chemotherapy)
             prior to initiation of study drugs

          -  Female patients of childbearing potential have a negative pregnancy test at baseline.
             Females of childbearing potential are defined as sexually mature women without prior
             hysterectomy or who have had any evidence of menses in the past 12 months. However,
             women who have been amenorrheic for 12 or more months are still considered to be of
             childbearing potential if the amenorrhea is possibly due to prior chemotherapy,
             anti-estrogens, or ovarian suppression

               -  Women of childbearing potential (i.e., menstruating women) must have a negative
                  urine pregnancy test (positive urine tests are to be confirmed by serum test)
                  documented within 14 days of treatment initiation

               -  Sexually active women of childbearing potential enrolled in the study must agree
                  to use 2 forms of accepted methods of contraception during the course of the
                  study and for 12 weeks after their last dose of study drug. Effective birth
                  control includes (a) intrauterine device plus 1 barrier method; (b) on stable
                  doses of hormonal contraception for at least 3 months (e.g., oral, injectable,
                  implant, transdermal) plus one barrier method; (c) 2 barrier methods. Effective
                  barrier methods are male or female condoms, diaphragms, and spermicides (creams
                  or gels that contain a chemical to kill sperm); or (d) a vasectomized partner

               -  For male patients who are sexually active and who are partners of premenopausal
                  women: agreement to use 2 forms of contraception as in criterion above during the
                  treatment period and for 12 weeks after the last dose of study drug

          -  Absolute neutrophil count >= 1,500/uL

          -  Platelet count >= 100,000/uL

          -  Hemoglobin >= 9.0 g/dL

          -  Total bilirubin =< 2 x upper limit of normal (ULN) or =< 3 x ULN for subjects with
             Gilbert?s disease or liver metastases

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN (=< 5 x
             ULN if evidence of hepatic involvement by malignant disease)

          -  Creatinine =< 1.5 x ULN or estimated glomerular filtration rate (eGFR) >= 40
             mL/min/1.73m^2

          -  Measurable disease according to irRECIST obtained by imaging within 28 days prior to
             treatment initiation

        Exclusion Criteria:

          -  Pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the pre-screening or screening visit
             through 23 weeks (female) or 31 weeks (male) after the last dose of study drug

          -  Treatment with any investigational agent within 28 days prior to registration for
             protocol therapy

          -  History of psychiatric illness or social situations that would limit compliance with
             study requirements. 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

          -  Known active, untreated central nervous system (CNS) metastases and/or carcinomatous
             meningitis except for patients with =< 3 small (< 0.6 cm) asymptomatic brain lesions
             where treatment is not indicated. Patients with neurological symptoms must undergo a
             head computed tomography (CT) scan or brain magnetic resonance imaging (MRI) to
             exclude brain metastasis. Patients whose brain metastases have been treated may
             participate provided they show radiographic stability (defined as 2 brain images
             obtained after treatment to the brain metastases at least 4 weeks apart and show no
             evidence of intracranial progression)

          -  Known history of human immunodeficiency virus (HIV) or active hepatitis B (by surface
             antigen expression or polymerase chain reaction [PCR]) or active hepatitis C (by PCR)
             infection

          -  Diagnosis of immunodeficiency or is receiving systemic steroid therapy (> 10 mg daily
             prednisone equivalent) or any other form of immunosuppressive therapy within 7 days
             prior to study registration

          -  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) or a documented history of clinically severe autoimmune disease, or a syndrome
             that requires systemic steroids or immunosuppressive agents. Vitiligo, alopecia,
             hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic
             treatment, celiac disease controlled by diet alone or conditions not expected to recur
             in the absence of an external trigger are permitted

          -  Documented history of a cerebral vascular event (stroke or transient ischemic attack),
             unstable angina, myocardial infarction, or cardiac symptoms consistent with New York
             Heart Association (NYHA) class III?IV within 6 months prior to their first dose of
             study drugs

          -  Prior malignancies (except non-melanoma skin cancers, and the following in situ
             cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or
             breast) unless a complete remission was achieved at least 1 year prior to study entry

          -  Any active grade 3 or higher viral, bacterial, or fungal infection within 2 weeks of
             the first dose of the study drugs. Routine antimicrobial prophylaxis is permitted

          -  Active diverticulitis

          -  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 CT scan.
             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:Assess the safety and tolerability of combined therapy in patients with metastatic NSCLC who have progressed on prior PD-1/PD-L1 therapy
Time Frame:Up to 30 days after the last dose of treatment
Safety Issue:
Description:Will include grade 3 and 4 toxicities as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

Secondary Outcome Measures

Measure:To determine objective response rate (ORR) of therapy
Time Frame:From the start of treatment until disease progression/recurrence, assessed up to 1 year
Safety Issue:
Description:Will be defined as the proportion of all subjected confirmed with an immune-related partial response (irPR) or immune-related complete response (irCR) divided by the number of assigned patients according to immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).
Measure:To estimate clinical benefit rate of the combination
Time Frame:Up to 1 year
Safety Issue:
Description:Will be defined as the percentage of patients who achieve irCR, irPR, and immune-related stable disease.
Measure:To estimate median progression-free survival (PFS) of the combination
Time Frame:From cycle 1, day 1 (each cycle is 21 days) of treatment until the criteria for disease progression is met as defined by irRECIST or death as a result of any cause, assessed up to 1 year
Safety Issue:
Description:The log-rank test will be used to analyze PFS for comparison of treatment effects, i.e., the only covariate that will be used is the treatment arm. Distributions of PFS times will be estimated using the Kaplan- Meier product-limit method. The median PFS times with two-sided 95% confidence intervals will be estimated for each treatment group.
Measure:To compare the frequency of immune-related adverse events (irAEs)
Time Frame:Up to 30 days after the last dose of treatment
Safety Issue:
Description:irAE's are defined as any treatment-related AE that is inflammatory in nature, consistent with the mechanism of action of immunotherapy and generally medically manageable with topical and/or systemic immunosuppressants.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Rutgers, The State University of New Jersey

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