Tremelimumab and Durvalumab With or Without Radiation Therapy in Patients With Relapsed Small Cell Lung Cancer

A Randomized Study of Tremelimumab Plus Durvalumab Combination With or Without Radiation in Relapsed Small Cell Lung Cancer

This randomized clinical trial studies how well tremelimumab and durvalumab with or without radiation therapy works in treating patients with small cell lung cancer that has returned after a period of improvement. Monoclonal antibodies, such as tremelimumab and durvalumab, may limit the ability of tumor cells to grow and spread by enhancing immune function. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving tremelimumab and durvalumab together with radiation therapy may lead to improved clinical benefit.

Study Overview

• Status: Completed
• Conditions: Recurrent Small Cell Lung Carcinoma
• Intervention / Treatment: Biological: Durvalumab; Radiation: Stereotactic Body Radiation Therapy; Biological: Tremelimumab; Radiation: Hypofractionated Radiation Therapy

Detailed Description

PRIMARY OBJECTIVE:

I. To assess the efficacy (progression free survival [PFS] and objective response rate [ORR]) of combined immune checkpoint inhibitor therapy as treatment for relapsed small-cell lung cancer (SCLC).

SECONDARY OBJECTIVES:

I. To assess the impact of antigen priming using radiation therapy (XRT) on the efficacy of immune checkpoint inhibitors.

II. To determine immune related objective response rate.

III. To estimate overall survival measured as time from randomization to death from any cause.

TERTIARY OBJECTIVES:

I. To characterize tumor infiltrating lymphocytes (TILs) and programmed cell death 1 ligand 1 (PD-L1)/programmed cell death 1 (PD1) expression in paired tumor biopsies at baseline, end of cycle 2 and at the time of progression.

II. To determine dynamic changes in cell free deoxyribonucleic acid (DNA) (cfDNA) and the immunophenotype of peripheral blood repertoire of circulating lymphocytes using multiparameter flow cytometry.

III. To determine changes in circulating cytokine mediators of inflammation and immunity using Luminex assay.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive tremelimumab intravenously (IV) over 1 hour on day 1. Treatment repeats every 4 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients also receive durvalumab IV over 1 hour on day 1. Treatment repeats every 4 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients achieving disease control may restart treatment upon evidence of progressive disease, with or without confirmation.

ARM II: Patients undergo radiation therapy daily for 5 days over 1 week or for 3 fractions every other day for 1 week and then receive the same treatment as in Arm I.

After completion of study treatment, patients are followed up periodically.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • Emory University Hospital Midtown
    • Atlanta, Georgia, United States, 30322
      • Emory University/Winship Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Written informed consent and any locally-required authorization (e.g.,) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
• Hemoglobin ≥ 9.0 g/dL
• Absolute neutrophil count (ANC) ≥ 1.5 x 10⁹/L (≥ 1500 per mm³)
• Platelet count ≥ 100 x 10⁹/L (≥ 100,000 per mm³)
• 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 clearance (CL) > 40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance
• Female subjects must either be of non-reproductive potential (i.e., post-menopausal by history: ≥ 60 years old and no menses for ≥ 1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy upon study entry
• 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 must have baseline evaluations performed prior to the first dose of study drug and must meet all inclusion and exclusion criteria
• Patients must have histologically or cytologically confirmed small cell lung cancer
• Patients must have measurable disease, defined as at least one lesion (excluding the lesion for XRT) that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as > 20 mm with conventional techniques or as > 10 mm with spiral computed tomography (CT) scan
• Patient must have failed or found to be intolerant of standard frontline platinum-based regimens and must not have received > 2 prior lines of therapy (nota bene [NB]: retreatment with a platinum-based doublet for sensitive relapse counts as another line therapy; however substitution of cisplatin with carboplatin or vice versa due to toxicity does not count as a separate regimen)
• Negative serum pregnancy test within 48 hours before starting study treatment in women with childbearing potential
• Ability to understand and the willingness to sign a written informed consent document

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 or randomization in the present study
• Treatment with an investigational product during the last 2 weeks
• Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4), including tremelimumab
• 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 prior to the first dose of study drug (≤ 7 days or four half-lives, whichever is longer, prior to the first dose of study drug for subjects who have received prior tyrosine kinase inhibitors [TKIs] [e.g., erlotinib, gefitinib and crizotinib] and within 6 weeks for nitrosourea or mitomycin C)
• Mean QT interval corrected for heart rate (QTc) ≥ 470 ms calculated from 3 electrocardiograms (ECGs) using Fredericia's Correction
• Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab or tremelimumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
• Any unresolved toxicity (> Common Terminology Criteria for Adverse Events [CTCAE] grade 2) from previous anti-cancer therapy; subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripherally neuropathy)
• Any prior grade ≥ 3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE > grade 1
• Active or prior documented autoimmune disease within the past 2 years; NOTE: subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded
• Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)
• History of primary immunodeficiency
• History of allogeneic organ transplant
• History of hypersensitivity to durvalumab or any excipient
• History of hypersensitivity to the combination or comparator agent
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent
• Known history of previous clinical diagnosis of tuberculosis
• History of leptomeningeal carcinomatosis
• Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab or tremelimumab
• Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control
• Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
• Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids
• 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, whichever is the longer time period
• Patients receiving any other investigational agents for any reason or non-investigational agents administered for the purpose of controlling cancer growth (use of conventional external beam radiation therapy will be allowed during protocol therapy solely for palliation of localized painful lesions or bone lesions at risk of fracture provided the radiation field does not encompass any selected target lesions required for assessment)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (tremelimumab, durvalumab); Patients receive tremelimumab IV over 1 hour on day 1. Treatment repeats every 4 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients also receive durvalumab IV over 1 hour on day 1. Treatment repeats every 4 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients achieving disease control may restart treatment upon evidence of progressive disease, with or without confirmation.	Biological: Durvalumab; Given IV; Other Names: MEDI4736; Biological: Tremelimumab; Given IV; Other Names: Anti-CTLA4 Human Monoclonal Antibody CP-675,206; CP-675,206; Ticilimumab
Active Comparator: Arm II (RT, tremelimumab, durvalumab); Patients undergo stereotactic body radiation therapy (SBRT) or hypofractionated radiation therapy daily for 5 days over 1 week or for 3 fractions every other day for 1 week and then receive the same treatment as in Arm I.	Biological: Durvalumab; Given IV; Other Names: MEDI4736; Radiation: Stereotactic Body Radiation Therapy; Undergo SBRT; Other Names: SBRT; Biological: Tremelimumab; Given IV; Other Names: Anti-CTLA4 Human Monoclonal Antibody CP-675,206; CP-675,206; Ticilimumab; Radiation: Hypofractionated Radiation Therapy; Undergo hypofractionated radiation therapy; Other Names: Hypofractionated Radiotherapy; Hypofractionation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	Time from initiation of therapy to objective disease progress or death	From initiation of systemic therapy to first documented disease progression, assessed through study completion, up to 2 years
Objective Response Rate	Disease response to therapy measured according to RECIST 1.1 criteria	After every 2 cycles of treatment (1 cycle = 4 weeks), assessed through study completion, up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immune-related Objective Response Rate	Disease response to treatment using immune-related response rate (irRR) criteria	Assessed after every 2 cycles (1 cycle = 4 weeks) on treatment; assessed through study completion, up to 2 years
Overall Survival	Time interval from entering the study until death	From randomization until death from any cause, assessed through study completion, up to 2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in the Proportion of Lymphocyte Subset (CD8+ICOS+) Between Baseline and On-Treament (End of Cycle 1)	Change in circulating and tumor-infiltrating lymphocytes between baseline and on-treatment samples at the end of Cycle 1. The proportion was calculated as the number of specific lymphocytes subset out of the total number of lymphocytes at baseline compared to the same proportion at the end of cycle 1.	Result presented for assessment at baseline and the end of cycle 1.

Collaborators and Investigators

• Sponsor: Emory University
• Collaborators: AstraZeneca
• Investigators: Principal Investigator: Taofeek Owonikoko, MD, PhD, Emory University

Publications and helpful links

General Publications

• Pakkala S, Higgins K, Chen Z, Sica G, Steuer C, Zhang C, Zhang G, Wang S, Hossain MS, Nazha B, Beardslee T, Khuri FR, Curran W, Lonial S, Waller EK, Ramalingam S, Owonikoko TK. Durvalumab and tremelimumab with or without stereotactic body radiation therapy in relapsed small cell lung cancer: a randomized phase II study. J Immunother Cancer. 2020 Dec;8(2):e001302. doi: 10.1136/jitc-2020-001302.

Helpful Links

• Journal Manuscript

Study record dates

Study Major Dates

• Study Start (Actual): April 14, 2016
• Primary Completion (Actual): August 7, 2020
• Study Completion (Actual): August 7, 2020

Study Registration Dates

• First Submitted: February 23, 2016
• First Submitted That Met QC Criteria: March 2, 2016
• First Posted (Estimate): March 8, 2016

Study Record Updates

• Last Update Posted (Actual): June 22, 2021
• Last Update Submitted That Met QC Criteria: May 28, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Small Cell Lung Carcinoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Durvalumab; Tremelimumab; Ipilimumab
• Other Study ID Numbers: IRB00086004; NCI-2016-00026 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); ESR-14-10531 (Other Identifier: AstraZeneca); Winship3112-15 (Other Identifier: Emory University/Winship Cancer Institute)