Tolerability and Efficacy of Tremelimumab in Combination With Gefitinib in NSCLC Patients

NCT02040064 | Completed Phase 1

• 2 other identifiers: 2013-003015-212013/2028
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open-label phase 1, safety, PK, and preliminary efficacy study of oral Gefitinib and IV Tremelimumab in previously treated NSCLC patients who have documented evidence of an activating mutation in the EGFR gene and have failed treatment with an EGFR inhibitor such as Erlotinib or Gefitinib. The primary objective of this phase I, is to determine the safety and tolerability of oral Gefitinib in combination with escalating doses of Tremelimumab and to establish a recommended phase 2 dose. Secondary objectives include evaluation of, pharmacokinetics, immunogenicity, antitumor activity of Gefitinib and Tremelimumab combination. The exploratory objectives are to evaluate biomarkers that may correlate with activity or prospectively identify patients likely to respond to Tremelimumab and Gefitinib. The biological rationale for such a study is that even though the disease is progressing it is likely that EGFR sensitive clones, although diminished under the pressure from the EGFR TKI, are still present. Therefore, withdrawing the inhibitory pressure of the EGFR TKI can potentially allow regrowth of the EGFR sensitive cells. On the other hand, the proliferation of EGFR resistant clones needs to be suppressed by another therapeutic approach. Until today no association of chemotherapy and TKI EGFR has demonstrated clinical benefit. Moreover, patients may have received chemotherapy and the likelihood of chemosensitivity is very low. So, the association of Gefitinib with immune checkpoint blockade is very attractive and may result in clinical benefit in NSCLC with EGFRmut.

Conditions

Non Small Cell Lung Cancer

Outcome Measures

Primary Outcomes (1)

• safety and tolerability of the association between Gefitinib (fixed dose) and Tremelimumab (dose escalation)

  The primary objective of this phase 1 study is to determine the safety and tolerability of oral Gefitinib in combination with three escalating doses of Tremelimumab and to establish a recommended phase 2 dose. Overall safety profile will be characterized by type, frequency, severity (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events \[NCICTCAE\] Version 4.03), timing of adverse events and laboratory abnormalities in the first and in the following cycles

  Up to 42 days

Secondary Outcomes (4)

• Anti-tumour activity of Gefitinib + Tremelimumab

  From day 1 cycle 1 every 8 weeks for 24 weeks and then every 6 weeks until progression or death whichever comes first assessed up to 30 months

• Immunogenicity of Tremelimumab in combination with Gefitinib

  At day 1 cycle 1 and then every 8 weeks from day 1 cycle 2 until progression or death whichever comes first assessed up to 30 months

• Pharmacokinetics of Gefitinib

  At first Tremelimumab administration and then every 4 weeks until progression or death whichever comes first assessed up to 30 months

• Pharmacokinetics of Tremelimumab

  Before and after injection of Tremelimumab at day 1 cycle 1 and at day 8 and day 15 of cycle 1 and then before and after injection at day 1 for every cycle (4 weeks) until progression or death whichever comes first assessed up to 30 months

Study Arms (1)

Treatment

EXPERIMENTAL

* Cohort 1: Tremelimumab 3 mg/kg every 4 Weeks plus Gefitinib 250 mg/daily, 6 patients (+ 6 patients if 3 mg/kg is the MTD) * Cohort 2: Tremelimumab 6 mg/kg every 4 Weeks plus Gefitinib 250 mg/daily, 6 patients (+ 6 patients if 6 mg/kg is the MTD) * Cohort 3: Tremelimumab 10 mg/kg every 4 Weeks plus Gefitinib 250 mg/daily, 6 patients (+ 6 patients if 10 mg/kg is the MTD)

Drug: Gefitinib; Drug: Tremelimumab

Interventions

Gefitinib DRUG

Oral tablet

Treatment

Tremelimumab DRUG

IV

Treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of written informed consent ;
• Female or male patients aged 18 years or over at the time of consent ;
• World Health Organisation (WHO) Performance Status 0 to 1 (Appendix C) ;
• Cytologically or histologically confirmed NSCLC with an activating EGFR TK mutations known to be associated with EGFR TKI sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) as determined locally using a well-validated and robust methodology ;
• Prior objective clinical benefit defined by either partial, complete or SD (\>/= 4months) after initiation of EGFR TKI treatment ;
• A washout period is not required for patients who are being treated with Gefitinib at the time of study entry. A washout period of at least 14 days is required for patients being treated with an irreversible EGFR TKI, chemotherapy, of at least 5 days for patients being treated with Erlotinib and at least five half-life for other treatments ;
• Locally advanced Stage IIIB not suitable for local therapy of curative intent or Stage IV (metastatic) disease ;
• At least one lesion, not previously irradiated and not chosen for fresh biopsy during the study screening period, that can be accurately measured at baseline as \>/= 10mm in the longest diameter (except lymph nodes which must have short access \>/= 15mm) with computerized tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate repeated measurements ;
• No standard therapy is considered appropriate. Prior treatment with chemotherapy is not mandated if either the patient refuses treatment with chemotherapy, or if, in the opinion of the investigator it is acceptable to delay treatment with chemotherapy ;
• Recovered from all toxicities associated with prior treatment, to acceptable baseline status, or a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade of 0 or 1, except for toxicities not considered a safety risk, such as alopecia or vitiligo ;
• Adequate bone marrow, hepatic, and renal function determined within 14 days prior to enrollment defined as:
• Platelet count \>/= 100,000/mm3
• Absolute neutrophil count \>/= 1,500/mm3
• Haemoglobin \>/= 9 g/dL
• Total bilirubin \</= 1.5 × ULN (upper limit of normal)

You may not qualify if:

• Known severe hypersensitivity to Gefitinib or any of the excipients of the product ;
• Previous EGFR TKI toxicity requiring discontinuation of treatment with the EGFR TKI (\> 4 weeks), or considered, by the investigator, to be difficult to manage ;
• Prior treatment with monoclonal antibody against CTLA-4, programmed cell death 1 (PD1) or programmed cell death 1 ligand 1 (PD-L1) ;
• Prior surgery or radiotherapy is allowed if completed more than 6 months before start of study treatment. Palliative radiotherapy must be completed at least 2 weeks before start of study treatment with no persistent radiation toxicity ;
• Considered to require radiotherapy to the lung at the time of study entry or in the near future ;
• Spinal cord compression or brain metastases unless asymptomatic, treated and stable, and not requiring steroids for at least 2 weeks prior to the start of study treatment ;
• Past medical history of interstitial lung disease, drug-induced interstitial disease, radiation pneumonitis which required steroid treatment or any evidence of clinically active interstitial lung disease ;
• Pre-existing idiopathic pulmonary fibrosis evidenced by CT scan at baseline ;
• Insufficient lung function as determined by either clinical examination or an arterial oxygen tension (PaO2) of \< 70 Torr ;
• Females who are pregnant or breastfeeding ;
• Any serious uncontrolled medical disorder or active infection that would impair the subject's ability to receive investigational product, such as conditions associated with frequent diarrhoea ;
• Clinically relevant cardiovascular disease, i.e., myocardial infarction or other severe coronary artery diseases within the prior 6 months, cardiac arrythmia requiring medication, uncontrolled hypertension, overt cardiac failure or not compensated chronic heart disease in NYHA class II or more ;
• Active or history of, diverticulitis. Note that diverticulosis is permitted ;
• Active or history of, inflammatory bowel disease (eg, colitis, Crohn's), irritable bowel disease, coeliac disease or other serious gastrointestinal chronic conditions associated with diarrhea ;
• Active, or history of, systemic lupus erythematosis or Wegener's granulomatosis ;

Sponsors & Collaborators

• Gustave Roussy, Cancer Campus, Grand Paris: lead
• AstraZeneca: collaborator

Study Sites (1)

Gustave Roussy

Villejuif, Val de Marne, 94805, France

Location

Related Publications (1)

• Riudavets M, Naigeon M, Texier M, Dorta M, Barlesi F, Mazieres J, Varga A, Cassard L, Boselli L, Grivel J, NgoCamus M, Lacroix L, Mezquita L, Besse B, Chaput N, Planchard D. Gefitinib plus tremelimumab combination in refractory non-small cell lung cancer patients harbouring EGFR mutations: The GEFTREM phase I trial. Lung Cancer. 2022 Apr;166:255-264. doi: 10.1016/j.lungcan.2021.11.018. Epub 2021 Dec 3.

  PMID: 34953624 DERIVED

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

Gefitinib; tremelimumab

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• David Planchard, MD

  Gustave Roussy, Cancer Campus, Grand Paris

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 10, 2014
• First Posted: January 20, 2014
• Study Start: January 1, 2014
• Primary Completion: March 1, 2016
• Study Completion: March 1, 2016
• Last Updated: June 9, 2016

Record last verified: 2016-06

Locations

FR (1)