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Stereotactic Body Radiation Therapy, Durvalumab, and Tremelimumab in Treating Patients with Stage IV Non-small Cell Lung Cancer

Trial Status: Active

This phase Ib trial studies the side effects of stereotactic body radiation therapy, durvalumab, and tremelimumab and to see how well they work in treating patients with stage IV non-small cell lung cancer. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method can kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Immunotherapy with monoclonal antibodies, such as durvalumab and tremelimumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving stereotactic body radiation therapy, durvalumab, and tremelimumab may work better in treating patients with non-small cell lung cancer.

Inclusion Criteria

  • Patients with histologically or cytologically confirmed stage IV NSCLC not amendable to curative surgery or radiation
  • Patients may have had prior chemotherapy or be chemotherapy naive
  • Patients must have tumors that lack sensitizing EGFR mutation (e.g. exon 19 deletion or exon 21 L858R) or ALK rearrangement; if a patient has squamous histology, then EGFR and ALK testing is not required
  • No prior treatment with cancer immunotherapy including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2 (PD-L2) antibodies, excluding therapeutic anticancer vaccines
  • Patients will have 6 or less extracranial sites, which can safely receive SBRT between 30 – 50 Gy in 5 fractions; a site may have multiple tumor lesions within it as long as the gross tumor volume (GTV) of the site is 8 cm or less and can be covered in an acceptable SBRT field determined by the principal investigator (PI); all gross disease (visible via imaging) must be amenable to treatment with SBRT, as allowable per normal tissue constraints; patients will not have had any prior radiation therapy significantly overlapping a tumor site to be treated
  • Patients must have evaluable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  • World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrollment
  • Life expectancy of >= 12 weeks
  • Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
  • Patients with treated metastatic lesions to the brain may be enrolled after completing stereotactic radiosurgery (may enroll 14 days after treatment) or whole brain radiation (may enroll 14 days after treatment) and must be off corticosteroids for at least 14 days prior to the start of SBRT
  • Hemoglobin >= 9.0 g/dL
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (>= 1500 per mm^3)
  • Platelet count >= 100 x 10^9/L (>= 100,000 per mm^3)
  • Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN); this will not apply to subjects with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be =< 5 x ULN
  • Serum creatinine < 1.5 x upper limit of normal (ULN) OR creatinine clearance (CrCl) >= 30 mL/min for subjects with creatinine levels >1.5 x institutional ULN
  • Female subject of childbearing potential should have a negative urine or serum pregnancy prior to receiving the first study treatment; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  • Female subjects of childbearing potential should be willing to use 1 method of highly effective birth control, 2 methods of effective birth control, be surgically sterile, or abstain from heterosexual activity for the course of the study through 180 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
  • Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients; women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause; the following age-specific requirements apply: * Women < 50 years of age would be considered post-menopausal if they have been amenorrhea for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy) * Women >= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced oophorectomy with last menses > 1 year ago, had chemotherapy-induced menopause with > 1 year interval since last menses, or underwent surgical sterilization (bilateral oophorectomy or hysterectomy)
  • Patient must be willing and able to provide written informed consent for the trial

Exclusion Criteria

  • Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
  • Previous enrollment in the present study
  • Mixed small-cell lung cancer
  • Any concurrent chemotherapy, investigational product (IP), biologic, or hormonal therapy for cancer treatment; concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable
  • Major surgical procedure (as defined by the investigator) within 14 days prior to the start of study treatment
  • Patients with untreated spinal cord compression; patients with spinal cord compression may be enrolled if stable after completing surgery (may enroll 14 days after surgery) or radiation (may enroll 14 days after treatment) and must be off corticosteroids for at least 14 days prior to the start of SBRT
  • Patients with untreated brain metastasis; patients with metastatic lesions to the brain may be enrolled after completing stereotactic radiosurgery or whole brain radiation (may enroll 14 days after treatment and must be off corticosteroids for at least 14 days prior to the start of SBRT)
  • Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an anti-CTLA4 inhibitor including tremelimumab
  • Patients with a known targetable EGFR mutation or ALK rearrangement
  • History of another primary malignancy except for: * Malignancy treated with curative intent and with no known active disease >= 2 years * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease * Non-metastatic prostate adenocarcinoma, or treated superficial non-invasive bladder cancer * Adequately treated carcinoma in situ without evidence of disease (e.g., cervical cancer in situ)
  • Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) =< 14 days of registration
  • Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) >= 470 ms; abnormality must be confirmed on 3 electrocardiography (ECG)s
  • Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab; the following are exceptions to this criterion: * Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra-articular injection) * Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent * Steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication)
  • Active or known autoimmune disease that has required immunosuppressive systemic treatment in 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) is not considered a form of systemic treatment and is allowed; the following are exceptions to this criterion: * Patients with vitiligo or alopecia * Graves disease * Hypothyroidism (e.g., following Hashimoto syndrome) * Psoriasis not requiring systemic treatment (within the past 2 years) * Type I diabetes mellitus * Patients with celiac disease controlled by diet alone
  • History of primary immunodeficiency
  • History of allogeneic organ transplant
  • Known history of previous clinical diagnosis of tuberculosis
  • Active infection, including tuberculosis (clinical evaluation), hepatitis B, hepatitis C, or human immunodeficiency virus (HIV, positive HIV 1 or 2 antibodies); active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen (HBsAg) result; patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible; patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
  • History of leptomeningeal carcinomatosis
  • Receipt of live attenuated vaccination within 30 days prior to the first dose of IP; Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of IP
  • Any condition or uncontrolled intercurrent illness that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results, including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring adverse event (AE)s from durvalumab or tremelimumab, or compromise the ability of the patient to give written informed consent
  • Subjects with uncontrolled seizures
  • Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose of durvalumab monotherapy
  • History of hypersensitivity to IP or comparator agents
  • History of medically diagnosed pneumonitis or interstitial lung disease

Wisconsin

Madison
University of Wisconsin Hospital and Clinics
Status: ACTIVE
Contact: Michael F. Bassetti
Phone: 608-263-8500

PRIMARY OBJECTIVE:

I. To determine the safety and tolerability of combined durvalumab and tremelimumab in combination with stereotactic body radiation therapy (SBRT) to all sites of disease in patients with 6 or less extracranial sites of oligometastatic non-small cell lung cancer (NSCLC).

SECONDARY OBJECTIVE:

I. To evaluate the potential benefit of SBRT to all metastatic sites combined with durvalumab and tremelimumab with respect to progression free survival (PFS), and overall survival (OS).

EXPLORATORY OBJECTIVES:

I. To determine whether immune response and PD-L1 expression on biopsy sections or circulating tumor cell (CTC)s is increased following SBRT and whether this correlates with tumor response, PFS, and OS.

II. To further understand the effects of treatment, both tumor biopsy and peripheral blood will be obtained before and after treatment.

OUTLINE:

Patients undergo SBRT for 5 fractions over 14 days. Within 7 days, patients receive tremelimumab intravenously (IV) over 1 hour and durvalumab IV over 1 hour on day 1. Treatment with durvalumab repeats every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, 2, 3, 4, 6, 8, 10, and 12 months, and then every 6 months thereafter.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
University of Wisconsin Hospital and Clinics

Principal Investigator
Michael F. Bassetti

  • Primary ID UW17003
  • Secondary IDs NCI-2017-01952, 2017-0665
  • Clinicaltrials.gov ID NCT03275597