A Phase I Study of Safety and Pharmacokinetics of Volitinib in Combination With Gefitinib in EGFR(+) NSCLC

NCT02374645 | Completed Phase 1 DMC

• 1 other identifier: D5080C00001
• Study Type: interventional
• Target: 64
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase 1b, open-label, multicentre study of AZD6094 in combination with gefitinib in patients with epidermal growth factor receptor (EGFR) mutation positive (m+) and progressed on EGFR Tyrosine kinase inhibitor (TKI) treatment.

Conditions

Non-Small Cell Lung Cancer

Outcome Measures

Primary Outcomes (1)

• Number of adverse events and serious adverse events

  the grade of AE event according to CTC AE 4.0

  From ICF signed to within 28 days after the last dose

Secondary Outcomes (4)

• The Pharmacokinetics (PK) profiles of AZD6094

  Cycle 1 Day1 and Day 15

• The Pharmacokinetics (PK) profiles of AZD6094

  Cycle 1 Day1 and Day 15

• Progression-free survival (PFS）

  from enrolled until progression or death due to any cause, assessed up to 2 year

• Disease control rate（DCR)

  12 weeks and 24 weeks

Study Arms (2)

Volitinib (AZD6094) 600mg + gefitinib 250 mg

EXPERIMENTAL

Cohort 1: Volitinib（AZD6094） 600 mg od + gefitinib 250 mg od

Drug: Volitinib; Drug: gefitinib

Volitinib (AZD6094) 800mg + gefitinib 250 mg

EXPERIMENTAL

Cohort 2: Volitinib（AZD6094） 800 mg od + gefitinib 250 mg od

Drug: gefitinib

Interventions

Volitinib DRUG

600mg or 800mg QD: Patients may continue to receive the treatment as long as they are continuing to show clinical benefit, as judged by the Investigator, and in the absence of discontinuation criteria.

Also known as: AZD6094, HMPL-504

Volitinib (AZD6094) 600mg + gefitinib 250 mg

gefitinib DRUG

250mg QD: Patients may continue to receive the treatment as long as they are continuing to show clinical benefit, as judged by the Investigator, and in the absence of discontinuation criteria.

Also known as: Iressa, ZD1839

Volitinib (AZD6094) 600mg + gefitinib 250 mg; Volitinib (AZD6094) 800mg + gefitinib 250 mg

Eligibility Criteria

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

You may qualify if:

• Provision of informed consent prior to any study specific procedures. If a patient declines to participate in any voluntary exploratory research and/or genetic component of the study there will be no penalty or loss of benefit to the patient and he or she will not be excluded from other aspects of the study.
• Male or female aged at least 18 years and older.
• Histologically or cytologically confirmed locally advanced or metastatic NSCLC patients who are harbouring an EGFR mutation known to be associated with EGFR-TKI sensitivity (including exon 19 deletion, L858R, L861Q, G719X). Local test for EGFR mutation is acceptable. In the expansion phase, patients must have a positive cMet test by a central laboratory. Safety run-in phase: EGFR mutation positive. A local EGFR test result is acceptable Expansion phase: EGFR mutation positive and cMet-positive. cMet test is performed by a central lab.
• Radiological documentation of disease progression while on a previous continuous treatment with EGFR-TKI eg, gefitinib or erlotinib. All patients must have documented radiological progression on the last treatment administered prior to enrolling in the study. The patients must have been treated with an EGFR-TKI with objective clinical benefit (CR/PR) or SD for 3 months, and who have subsequently shown radiological progression on treatment. In addition, other lines of therapy may have been given.
• At least 1 lesion, not previously irradiated, not biopsied during the screening period, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have short axis ≥15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate repeated measurements.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks.
• Women should agree to use adequate contraceptive measures (as defined in section 5.1), should not be breast feeding, and must have a negative pregnancy test prior to start of dosing or if of child-bearing potential or of non-child- bearing potential must have evidence of this by fulfilling 1 of the following criteria at screening:
• Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments
• Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
• Women under 50 years of age would be considered postmenopausal if they have been amenorrhoeic for at least 12 months following the cessation of exogenous hormonal treatments, and have serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels in the postmenopausal range for the institution.
• Sexually active male patients should be willing to use barrier contraception; ie, condoms.

You may not qualify if:

• Intervention with any of the following:
• Treatment with an EGFR-TKI within approximately 5x half-life (eg, within 8 days for erlotinib, gefitinib or afatanib, within 10 days for dacomitinib) of the first dose of study treatment
• Any cytotoxic chemotherapy, investigational agents or other anticancer drugs for the treatment of advanced NSCLC from a previous treatment regimen or clinical study within 14 days of the first dose of study treatment
• Patients currently receiving (or unable to stop use at least 2 weeks) prior to receiving the first dose of AZD6094, medications known to be strong inhibitors of CYP1A2 (Appendix E)
• Prior or current treatment with AZD6094 or another cMet inhibitor (eg, foretinib, crizotinib, cabozantinib, onartuzumab)
• Concurrent use of hormones for non-cancer-related conditions (eg, insulin for diabetes and hormone replacement therapy) is acceptable.
• Radiotherapy with a limited field of radiation for palliation within 1 week of the first dose of study treatment, with the exception of patients receiving radiation to more than 30% of the bone marrow or with a wide field of radiation which must be completed ≥4 weeks of the first dose of study treatment.
• Major surgical procedure, (excluding placement of vascular access) or significant traumatic injury within 4 weeks of the first dose of study treatment, or have an anticipated need for major surgery during the study
• With the exception of alopecia and CTCAE Grade 2, prior chemotherapy-related neuropathy, any unresolved toxicities from prior therapy and/or pre-study biopsies greater than CTCAE Grade 1 at the time of starting study treatment
• Have non-measurable disease at baseline per RECIST v1.1. To ensure that the patient will be able to complete the evaluable period of the study and the assessment of progression can be performed according to the RECIST v1.1 criteria and the relevant treatment decisions applied OR can be summarised for patients with measurable disease at baseline
• Presence of other active cancers, or history of treatment for invasive cancer ≤5 years. Patients with Stage I cancer who have received definitive local treatment at least 3 years previously, and are considered unlikely to recur are eligible. All patients with previously treated in situ carcinoma (i.e., non-invasive) are eligible, as are patients with history of non-melanoma skin cancer.
• Current leptomeningeal metastases or spinal cord compression. Brain metastases are only permitted if treated, asymptomatic, and stable (not requiring steroids for at least 4 weeks prior to start of study treatment).
• Patients with known tumour thrombus or deep vein thrombosis are eligible if stable on low molecular weight heparin for ≥4 weeks.
• As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, renal transplant, active bleeding diatheses, which in the Investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol; including evidence of active infection including hepatitis B (HBV) surface antigen, hepatitis C virus (HCV) antibody or human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
• Any serious uncontrolled medical disorder or active infection that would impair the patient's ability to receive IP, such as conditions associated with frequent diarrhoea.

Sponsors & Collaborators

• Hutchison Medipharma Limited: lead
• AstraZeneca: collaborator

Study Sites (1)

Guangdong General Hospital

Guangzhou, 510080, China

Location

Related Publications (1)

• Yang JJ, Fang J, Shu YQ, Chang JH, Chen GY, He JX, Li W, Liu XQ, Yang N, Zhou C, Huang JA, Frigault MM, Hartmaier R, Ahmed GF, Egile C, Morgan S, Verheijen RB, Mellemgaard A, Yang L, Wu YL. A phase Ib study of the highly selective MET-TKI savolitinib plus gefitinib in patients with EGFR-mutated, MET-amplified advanced non-small-cell lung cancer. Invest New Drugs. 2021 Apr;39(2):477-487. doi: 10.1007/s10637-020-01010-4. Epub 2020 Oct 14.

  PMID: 33052556 DERIVED

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

1-(1-(imidazo(1,2-a)pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-(1,2,3)triazolo(4,5-b)pyrazine; Gefitinib

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

• Yilong Wu, Prof.

  Guangdong Provincial People's Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 12, 2015
• First Posted: March 2, 2015
• Study Start: April 1, 2015
• Primary Completion: February 18, 2018
• Study Completion: September 14, 2018
• Last Updated: April 24, 2020

Record last verified: 2020-04

Locations

CN (1)