Clinical trial NCT03057106: Durvalumab and Tremelimumab ± Platinum-Based Chemotherapy in Patients With Metastatic Squamous or Non-Squamous NSCLC
Official title: A Randomized Trial of Durvalumab and Tremelimumab ± Platinum-Based Chemotherapy in Patients With Metastatic (Stage IV) Squamous or Non-Squamous Non-Small Cell Lung Cancer (NSCLC)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Lung Cancer Metastatic
Lead sponsor: Canadian Cancer Trials Group
Sponsor class: NETWORK
Collaborators: name: AstraZeneca
name: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
name: National Health and Medical Research Council, Australia
First posted: 2017-02-17
Enrollment: 301
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Durvalumab is a new type of drug for many kinds of cancer. It is considered "immunotherapy" and not "chemotherapy". Laboratory tests show that it works by allowing the immune system to detect cancer and reactivate the immune response. This may help to slow down the growth of cancer or may cause cancer cells to die. Durvalumab has been shown to shrink tumours in animals and has been studied in more than 5000 people and seems promising.

Tremelimumab is a new type of drug for various types of cancers. It works in a similar way to durvalumab and may improve the effect of durvalumab. Tremelimumab may also help slow the growth of the cancer cells or may cause cancer cells to die. It has been shown to shrink tumours in animals and has been studied in over 1200 people and seems promising.

Detailed description: Combinations of durvalumab and tremelimumab have also been studied. While the combination has been studied in over 200 people, it is not clear if it can offer better results when it is combined with chemotherapy.

Recently, immunotherapies that target the PD-1/PD-L1 axis have shown promise in treating patients with non-small cell lung cancer.

Eligibility criteria: Inclusion Criteria:

* Patients must have histologically and/or cytologically confirmed diagnosis of squamous or non-squamous, non-small cell carcinoma of the lung. Patients with poorly differentiated tumours will only be eligible if NSCLC is confirmed by immunohistochemistry markers (TTF1/P63 or P40/CK5). Patients with known sensitizing EGFR mutations or known ALK-fusion are not eligible.
* Patients must have stage IV disease according to the 8th TNM version staging.
* Patients must have an adequate histopathology specimen and must consent to release this specimen for protocol required testing. This is a mandatory component of the study.
* Patient must consent to provision of samples of blood in order that the specific correlative marker assays proscribed may be conducted.
* All patients must have measurable disease as defined by RECIST 1.1 All radiology studies must be performed within 28 days prior to randomization (within 35 days if negative).

The criteria for defining measurable disease are as follows:

* CT scan (with slice thickness of 5 mm) ≥ 10 mm --\> longest diameter
* Physical exam (using calipers) ≥ 10 mm
* Lymph nodes by CT scan ≥ 15 mm --\> measured in short axis

Measurable lesions must be outside a previous radiotherapy field if they are the sole site of disease, unless disease progression has been documented.

* Patients must be 18 years of age or older.
* ECOG performance status of 0 or 1.
* Absolute neutrophils ≥ 1.5 x 10\^9/L
* Platelets ≥ 100 x 10\^9/L
* Hemoglobin ≥ 90 g/L
* Bilirubin ≤ 1.5 x UNL (upper limit of normal)
* AST and ALT ≤ 2.5 x UNL (if liver metastases are present, ≤5 x UNL) Creatinine \< 1.25 UNL or Creatinine clearance ≥ 45 mL/min
* Cytotoxic Chemotherapy: Patients may not have received prior cytotoxic chemotherapy for advanced/metastatic disease.
* Adjuvant Chemotherapy: Patients may have had prior adjuvant therapy for completely resected disease, providing it has been completed at least 12 months prior to randomization.
* Patients treated with concurrent chemotherapy/radiation regimens for unresectable locally advanced Stage III disease will be eligible providing it has been completed at least 12 months prior to randomization.
* Other Systemic Therapy: Patients may not have received prior EGFR or alk inhibitors. Patients may not have received prior treatment with immune-based therapy, including durvalumab and tremelimumab vaccines or oncolytic viral therapy. Patients must have recovered from any reversible treatment related toxicities prior to randomization.
* Prior external beam radiation is permitted provided a minimum of 14 days (2 weeks) have elapsed between the last dose of radiation and date of randomization. Concurrent radiotherapy is not permitted.

Patients must have recovered from any acute toxic effects from radiation prior to randomization.

* Patients must have recovered from any acute toxic effects from radiation prior to randomization.
* Surgery: Previous surgery is permitted provided that wound healing has occurred and at least 14 days have elapsed (major surgery) prior to randomization.
* Patient must be able (i.e. sufficiently fluent) and willing to complete the quality of life and health economics questionnaires.
* Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements.
* Patients must be accessible for treatment and follow-up. All randomized patients must be followed and treated at participating centres.
* In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient randomization.
* Female patients of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception while on study and for 6 months after the last dose of durvalumab and tremelimumab or for 3 months after the last dose of durvalumab alone

Exclusion Criteria:

* Patients with a history of other malignancies, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for ≥ 3 years. Patients with a history of other malignancies detected at an early stage and whom the investigator believes have been curatively treated and are at low risk of recurrence MAY be eligible. Contact CCTG to discuss eligibility prior to enrolling.
* Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease (e.g. colitis or Crohn's disease), diverticulitis with the exception of diverticulosis, celiac disease or other serious gastrointestinal chronic conditions associated with diarrhea), systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis), rheumatoid arthritis, hypophysitis, uveitis, etc., within the past 3 years prior to the start of treatment. The following are exceptions to this criterion:

  * Patients with alopecia.
  * Patients with Grave's disease, vitiligo or psoriasis not requiring systemic treatment (within the last 2 years).
  * Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement.
* History of primary immunodeficiency, history of allogenic organ transplant that requires therapeutic immunosuppression and the use of immunosuppressive agents within 28 days of randomization\* or a prior history of severe (grade 3 or 4) immune mediated toxicity from other immune therapy or grade ≥ 3 infusion reaction.
* Live attenuated vaccination administered within 30 days prior to randomization
* History of hypersensitivity to durvalumab or tremelimumab or any excipient. Patients who have received other treatment or other antibodies must not have had intolerable toxicity or required steroids to manage toxicity.
* Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 470 msec in screening ECG measured using standard institutional method or history of familial long QT syndrome.
* Patients who have untreated and/or uncontrolled cardiovascular conditions and/or have symptomatic cardiac dysfunction (unstable angina, congestive heart failure, myocardial infarction within the previous year or cardiac ventricular arrhythmias requiring medication, history of 2nd or 3rd degree atrioventricular conduction defects). Patients with a significant cardiac history, even if now controlled, should have a LVEF ≥ 45%. (Note: patients with uncomplicated controlled hypertension do not require LVEF measurement in the absence of other significant cardiac history)
* Concurrent treatment with other investigational drugs or anti-cancer therapy
* Patients with untreated brain or meningeal metastases are not eligible. Patients with treated CNS disease who have radiologic AND clinical evidence of stable brain metastases, with no evidence of cavitation or hemorrhage in the brain lesion, are eligible providing that they are asymptomatic and do not require corticosteroids (must have discontinued steroids at least 1 week prior to randomization).
* Pregnant or Lactating Women: Women of childbearing potential must have a pregnancy test (urine or serum) proven negative within 14 days prior to randomization. If urine test is positive, pregnancy testing may then include an ultrasound to rule-out pregnancy if a false-positive is suspected. For example, when beta-human chorionic gonadotropin is high and partner is vasectomized, it may be associated with tumour production of hCG, as seen with some cancers. Patient will be considered eligible if an ultrasound is negative for pregnancy. Men and women of child-bearing potential must agree to use adequate contraception.
* Patients with serious illnesses or medical conditions which would not permit the patient to be managed according to the protocol (including corticosteroid administration), or would put the patient at risk. This includes but is not limited to:

  * Contraindications to the use of pemetrexed, gemcitabine, cisplatin and/or carboplatin (consult product monograph);
  * History of significant neurologic or psychiatric disorder which would impair the ability to obtain consent or limit compliance with study requirements;
  * Active infection requiring systemic therapy; (including any patient known to have active hepatitis B, hepatitis C or human immunodeficiency virus (HIV) or tuberculosis);
  * Active peptic ulcer disease or gastritis;
  * Known pneumonitis or pulmonary fibrosis with clinically significant impairment of pulmonary function.

Primary outcomes:
measure: Overall Survival
timeFrame: 33 months
Secondary outcomes:
measure: Progression-free Survival Using RECIST 1.1
timeFrame: 33 months
measure: Objective Response Rate Using RECIST 1.1 and iRECIST
timeFrame: 33 months
Other outcomes:
Locations:
city: Campbelltown
country: Australia
facility: Campbelltown Hospital
state: New South Wales
city: Coffs Harbour
country: Australia
facility: Coffs Habour Health Campus - NCCI
state: New South Wales
city: Concord
country: Australia
facility: Concord Repatriation General Hospital
state: New South Wales
city: Kingswood
country: Australia
facility: Nepean Hospital
state: New South Wales
city: Kogarah
country: Australia
facility: St. George Hospital, Cancer Care Centre
state: New South Wales
city: Lismore
country: Australia
facility: The Tweed Hospital
state: New South Wales
city: Liverpool
country: Australia
facility: Liverpool Cancer Therapy Centre, Liverpool Hospital
state: New South Wales
city: Randwick
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: Brisbane
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Chermside
country: Australia
facility: The Prince Charles Hospital
state: Queensland
city: South Brisbane
country: Australia
facility: Mater Research Institute South Brisbane
state: Queensland
city: Southport
country: Australia
facility: Gold Coast University Hospital
state: Queensland
city: Toowoomba
country: Australia
facility: Toowoomba Hospital
state: Queensland
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Ballarat
country: Australia
facility: Ballarat Health Services
state: Victoria
city: Richmond
country: Australia
facility: Epworth HealthCare - Richmond
state: Victoria
city: Wodonga
country: Australia
facility: Border Medical Oncology
state: Victoria
city: Subiaco
country: Australia
facility: Saint John of God Hospital Subiaco
state: Western Australia
city: Victoria Park
country: Australia
facility: St. Vincent's Hospital
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Surrey
country: Canada
facility: BCCA - Fraser Valley Cancer Centre
state: British Columbia
city: Vancouver
country: Canada
facility: BCCA - Vancouver Cancer Centre
state: British Columbia
city: Fredericton
country: Canada
facility: Horizon Health Network
state: New Brunswick
city: Moncton
country: Canada
facility: The Moncton Hospital
state: New Brunswick
city: Moncton
country: Canada
facility: The Vitalite Health Network - Dr. Leon Richard
state: New Brunswick
city: Saint John
country: Canada
facility: Regional Health Authority B, Zone 2
state: New Brunswick
city: Cambridge
country: Canada
facility: Cambridge Memorial Hospital
state: Ontario
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre at Hamilton Health Sciences
state: Ontario
city: Kingston
country: Canada
facility: Kingston Health Sciences Centre
state: Ontario
city: Kitchener
country: Canada
facility: Grand River Regional Cancer Centre
state: Ontario
city: Newmarket
country: Canada
facility: Stronach Regional Health Centre at Southlake
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital Research Institute
state: Ontario
city: Sault Ste. Marie
country: Canada
facility: Algoma District Cancer Program
state: Ontario
city: St. Catharines
country: Canada
facility: Niagara Health System
state: Ontario
city: Sudbury
country: Canada
facility: Health Sciences North
state: Ontario
city: Toronto
country: Canada
facility: North York General Hospital
state: Ontario
city: Toronto
country: Canada
facility: Humber River Regional Hospital
state: Ontario
city: Toronto
country: Canada
facility: Michael Garron Hospital
state: Ontario
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
city: Windsor
country: Canada
facility: Windsor Regional Cancer Centre
state: Ontario
city: Charlottetown
country: Canada
facility: PEI Cancer Treatment Centre
state: Prince Edward Island
city: Laval
country: Canada
facility: Hopital de la Cite-de-la-Sante
state: Quebec
city: Montreal
country: Canada
facility: CHUM-Centre Hospitalier de l'Universite de Montreal
state: Quebec
city: Montreal
country: Canada
facility: The Jewish General Hospital
state: Quebec
city: Quebec City
country: Canada
facility: CHU de Quebec-Hopital l'Enfant-Jesus (HEJ)
state: Quebec
city: Quebec City
country: Canada
facility: University Institute of Cardiology and
state: Quebec
city: Sherbrooke
country: Canada
facility: Centre hospitalier universitaire de Sherbrooke
state: Quebec
city: Regina
country: Canada
facility: Allan Blair Cancer Centre
state: Saskatchewan
city: Saskatoon
country: Canada
facility: Saskatoon Cancer Centre
state: Saskatchewan
Study officials:
affiliation: Princess Margaret Hospital, Toronto, ON Canada
name: Natasha Leighl
role: STUDY_CHAIR
References:
citation: Leighl NB, Laurie SA, Goss GD, Hughes BGM, Stockler M, Tsao MS, Hwang DM, Joubert P, Kulkarni S, Blais N, Joy AA, Mates M, Rana P, Yadav SK, Underhill C, Lee C, Bradbury PA, Hiltz A, Dancey J, Ding K, Vera-Badillo F; Canadian Cancer Trials Group Lung Disease Site and the Australasian Lung Cancer Trials Group. CCTG BR34: A Randomized Phase 2 Trial of Durvalumab and Tremelimumab With or Without Platinum-Based Chemotherapy in Patients With Metastatic NSCLC. J Thorac Oncol. 2022 Mar;17(3):434-445. doi: 10.1016/j.jtho.2021.10.023. Epub 2021 Nov 17.