Phase 1b dose escalation and dose expansion study in patients with advanced or metastatic non-small cell lung cancer (NSCLC)
| ISRCTN | ISRCTN99682126 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN99682126 |
| EudraCT/CTIS number | 2021-005831-22 |
| IRAS number | 1005456 |
| Secondary identifying numbers | FURMO-002, IRAS 1005456, CPMS 52527 |
- Submission date
- 11/05/2022
- Registration date
- 04/08/2022
- Last edited
- 10/10/2023
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Cancer
Plain English summary of protocol
Background and study aims
The purpose of this study is to learn about how the study drug, furmonertinib, works in participants with non-small cell lung cancer (NSCLC) who have a mutation in a specific gene and how it may help them. For participants with this type of NSCLC, the study will help researchers to learn how safe the study drug is, to learn how much of the study drug to give to patients, and to compare the effects, good or bad, of the study drug.
Globally, lung cancer is the second most commonly diagnosed cancer and the leading cause of cancer-related deaths among men and women, with an estimated 2.2 million new cancer cases and 1.8 million deaths reported in 2020. NSCLC is the predominant subtype of lung cancer, accounting for approximately 85% of all cases.
Who can participate?
Up to about 108 men and women (aged 18 years or over) with NSCLC may take part in this study. Patients that have NSCLC that has spread and has not responded to treatment or for which previous treatment was stopped because they could not tolerate the side effects would be eligible to take part.
What does the study involve?
This study has three parts:
1. Screening (to see if you are eligible for the study)
2. Treatment
3. Follow-up (to check on you after treatment is finished)
The study has a dose escalation phase, which will try to establish the maximum tolerated dose of the study drug, with up to 48 participants; and a dose expansion phase, which will collect further data on participants with different tumour mutations, with up to 60 participants.
The total time for a participant to be in the study will depend on how their lung cancer responds to treatment. This could range from 1 day to up to 48 months.
What are the possible benefits and risks of participating?
Benefits:
Not provided at time of registration
Risks:
As with all studies the drug treatment and other therapies may involve risks that are known as well as risks that are currently unknown. Participants will be carefully monitored for any side effects, however not all of the side effects that the study drug may have are known. Side effects may range from mild to serious, and in some cases side effects may be long-lasting or permanent or may even be life-threatening. Taking part in the study involves some risks and possible discomfort to participants, and this is explained in the Participant Information Sheet.
Where is the study run from?
Syneos Health UK Limited
When is the study starting and how long is it expected to run for?
May 2022 to April 2026
Who is funding the study?
ArriVent BioPharma, Inc. (USA)
Who is the main contact?
Dr Martin Forster, martin.forster1@nhs.net
Nichole Baio, BaioN@ArriVent.com
Contact information
Scientific
Farnborough Business Park
1 Pinehurst Road
Farnborough
GU14 7BF
United Kingdom
| Phone | +44 1276 713023 |
|---|---|
| SM_UKcountrySSU@syneoshealth.com |
Principal Investigator
235 Euston Road
London
NW1 2BU
United Kingdom
| Phone | +44 20 3447 5085 |
|---|---|
| martin.forster1@nhs.net |
Scientific
18 Campus Blvd.
Suite 100
Newtown Square
19073-3269
United States of America
| Phone | +1 781-424-3702 |
|---|---|
| BaioN@ArriVent.com |
Study information
| Study design | Dose escalation study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Non randomised study |
| Study setting(s) | Other |
| Study type | Treatment |
| Scientific title | A phase 1b dose escalation and dose expansion study evaluating the safety, pharmacokinetics, and antitumor activity of furmonertinib in patients with advanced or metastatic non-small cell lung cancer (NSCLC) with activating EGFR or HER2 mutations, including exon 20 insertion mutations |
| Study objectives | - To evaluate the safety, tolerability, including estimation of the maximal tolerated dose (MTD), determination of the expansion dose, and characterization of dose limiting toxicities (DLTs) of escalating doses of furmonertinib administered daily to patients with locally advanced or metastatic NSCLC - To make a preliminary assessment of the antitumor activity of furmonertinib - To evaluate the safety and tolerability of furmonertinib at the expansion dose - To characterize the pharmacokinetic (PK) properties of furmonertinib and its major metabolite (AST5902) |
| Ethics approval(s) | Approval pending, ref: 22/EM/0118 |
| Health condition(s) or problem(s) studied | Patients with Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) with mutations in a gene called epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2). |
| Intervention | All participants will receive the study drug. Depending on the dose group to which they e assigned, participants will take a dose consisting of 4, 6, or 8 pills of the study drug, furmonertinib (each pill is 40 mg strength), each day, at approximately the same time, on an empty stomach. The study drug is to be taken daily in treatment cycles of 21 days (one cycle = 21 days/3weeks) |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase I |
| Drug / device / biological / vaccine name(s) | furmonertinib |
| Primary outcome measure | Incidence and severity of adverse events (AEs) including DLTs, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) during the study |
| Secondary outcome measures | 1. Confirmed objective response rate (ORR), defined as the percentage of patients with a confirmed complete response (CR) or partial response (PR) relative to the total number of patients. Confirmation of the response is based on two consecutive assessments, at least 28 days apart, as determined by investigator assessment and blinded independent central review (BICR) assessment using RECIST v1.1 2. Duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and depth of response (DpR) evaluated by investigator assessment and by BICR per RECIST v1.1 3. Overall survival (OS) 4. Central nervous system (CNS) confirmed ORR (CNS ORR) and DOR (CNS DOR) via RECIST v1.1 by BICR 5. Change from baseline in safety-related clinical laboratory test results 6. Plasma concentrations of furmonertinib and its major metabolite (AST5902) at specified timepoints 7. Change from baseline in patient-reported symptoms and their impact on functioning and health-related quality of life, and the overall burden of side effects, as measured by the European Organization for Research and Treatment of Cancer Quality of Life Core 30 Questionnaire (EORTC QLQ-C30) and EORTC QLQ-LC13, and Non-Small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC SAQ) 8. Correlation of PK with primary, secondary, exploratory endpoints in patients treated with furmonertinib 9. Change in tumour tissue gene profile at baseline, during treatment, and at disease progression 10. Consistency and change of ctDNA gene profile in the peripheral blood at baseline, during treatment, and disease progression samples 11. EGFR mutation status in ctDNA in peripheral blood or possible changes in resistant gene profile at baseline, during treatment, and at disease progression |
| Overall study start date | 09/05/2022 |
| Completion date | 01/04/2026 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 108 |
| Key inclusion criteria | 1. Signed Informed Consent Form 2. Age ≥18 years at time of signing Informed Consent Form 3. Ability to comply with the study protocol, in the investigator’s judgment 4. Measurable disease per RECIST v1.1 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 6. Life expectancy of ≥ 12 weeks 7. Adequate hematologic and organ function within 14 days prior to initiation of study treatment 8. For women of childbearing potential (WOCBP): Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs 9. For men who are not surgically sterile: Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating sperm 10. Patients with a history of treated CNS metastases or new asymptomatic CNS metastases detected at screening 11. Histologically or cytologically documented, locally advanced or metastatic NSCLC not amenable to curative surgery or radiotherapy 12. Consent to provide tumor tissue specimen (paraffin-embedded tissue block or 15 serial-cut slides) 13. Disease that has progressed after at least one available standard therapy; or for whom standard therapy has proven to be ineffective or intolerable; or for whom a clinical trial of an investigational agent is a recognized standard of care 14. Documented radiologic disease progression during or after the last systemic antitumor therapy before the first dose of the investigational product (furmonertinib) 15. For patients with EGFR mutations sensitive to osimertinib, the patient must have received osimertinib prior to study enrollment in regions where osimertinib is approved, including the US Stage 1 Dose Escalation and Backfill Cohorts Inclusion Criteria: 16. Documented validated results from local testing of blood or tumor tissue confirming the presence of an EGFR Exon 20 insertion mutation, HER2 Exon 20 insertion mutation, or EGFR activating mutation (including Exon 19 and Exon 21 mutations such as G719X, Exon 19 deletion, L858R, L861Q) or EGFR T790M mutation 17. For patients with NSCLC with EGFR Exon 20 insertion mutations or HER2 Exon 20 insertion mutations, the patient must have experienced disease progression (during or after treatment) or have intolerance to treatment with platinum-based chemotherapy 18. For patients with NSCLC with EGFR activating mutations other than Exon 20 insertion mutations, the patient must have experienced disease progression (during or after treatment) with the standard of care EGFR TKI Stage 2 Cohort 1 Inclusion Criteria: 19. Documented validated results from either local testing of blood or tumor tissue confirming the presence of EGFR Exon 20 insertion mutations 20. The patient must have experienced disease progression (during or after treatment) or have intolerance to treatment with platinum-based chemotherapy Stage 2 Cohort 2 Inclusion Criteria: 21. Documented validated results from either local testing of blood or tumor tissue confirming the presence of HER2 Exon 20 Insertion Mutations 22. The patient must have experienced disease progression (during or after treatment) or have intolerance to treatment with platinum-based chemotherapy Stage 2 Cohort 3 Inclusion Criteria: 23. Documented validated results from either local testing of blood or tumor tissue confirming the presence of an EGFR activating mutation (including Exon 19 and Exon 21 mutations such as G719X, Exon 19 deletion, L858R, L861Q) or EGFR T790M mutation 24. The patient must have experienced disease progression (during or after treatment) or have intolerance to treatment with the standard of care EGFR TKI |
| Key exclusion criteria | 1. Inability or unwillingness to swallow pills 2. Inability to comply with study and follow-up procedures 3. Malabsorption syndrome or other condition that would interfere with enteral absorption 4. Pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures biweekly or more frequently 5. Severe acute or chronic infections 6. In the setting of a pandemic or epidemic, screening for active infections should be considered according to local or institutional guidelines or those of applicable professional societies 7. Previous interstitial lung disease (ILD), drug-induced interstitial lung disease, radiation pneumonitis requiring steroid therapy; or having the clinical manifestations of suspected ILD. 8. History of or active clinically significant cardiovascular dysfunction 9. Mean resting corrected QT interval (QTcF) > 470 msec, obtained from triplicate ECGs, using the screening clinic ECG machine derived QTcF value. 10. Clinically significant prolonged QT interval or other arrhythmia or clinical status considered by investigators that may increase the risk of prolonged QT interval or current use of the drugs that may lead to prolonged QT interval 11. Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or calcium > 12 mg/dL or corrected serum calcium ≥ ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab. 12. Significant traumatic injury or major surgical procedure within 4 weeks prior to Day 1 of Cycle 1. 13. Patients with chronic diarrhea, short bowel syndrome or significant upper gastrointestinal surgery including gastric resection, a history of inflammatory bowel disease or any active bowel inflammation (including diverticulitis) 14. Any other diseases, active or uncontrolled pulmonary dysfunction, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of furmonertinib, that may affect the interpretation of the results, or renders the patients at high risk from treatment complications 15. Treatment with chemotherapy, immunotherapy, biologic therapy, or an investigational agent as anti-cancer therapy within 3 weeks or five half-lives prior to initiation of furmonertinib, whichever is shorter, or endocrine therapy within 2 weeks prior to initiation of furmonertinib 16. Radiation therapy (other than palliative radiation to bony metastases and radiation to CNS metastases as described above) as cancer therapy within 4 weeks prior to initiation of furmonertinib 17. Palliative radiation to bony metastases within 2 weeks prior to initiation of furmonertinib 18. Adverse events from prior anti-cancer therapy that have not resolved to Grade ≤ 1 except for alopecia or Grade ≤ 2 peripheral neuropathy 19. History of other malignancy within 3 years prior to screening, with the exception of patients with a negligible risk of metastasis or death and/or treated with expected curative outcome 20. Pregnant, breastfeeding, or intending to become pregnant during the study or within 60 days after the final dose of furmonertinib 21. Known or suspected allergy to furmonertinib or other components of its preparation 22. Use of a potent CYP3A4 inhibitor within 7 days prior to the first dose of investigational product or a potent CYP3A4 inducer within 21 days prior to the first dose of furmonertinib 23. Use of an herbal medicine within 2 weeks prior to the first dose of furmonertinib, or if herbal medicine is expected to be used during the study In addition to the general exclusion criteria, patients who meet any of the additional criteria listed below will be excluded from entry into specific cohorts: Stage 2 Cohort 3 Exclusion Criteria: 24. NSCLC patients with a documented EGFR Exon 20 insertion mutation by a local test (tumor tissue or blood) |
| Date of first enrolment | 31/03/2022 |
| Date of final enrolment | 31/10/2023 |
Locations
Countries of recruitment
- Australia
- Japan
- Spain
- United Kingdom
Study participating centre
250 Euston Road
London
NW1 2PG
United Kingdom
Sponsor information
Industry
1 Pinehurst Road
Farnborough Business Park
Farnborough
GU14 7BF
England
United Kingdom
| Phone | +44 1276 713000 |
|---|---|
| furmo@arrivent.com |
Funders
Funder type
Industry
No information available
Results and Publications
| Intention to publish date | 01/04/2027 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not expected to be made available |
| Publication and dissemination plan | Peer reviewed scientific journals Internal report Conference presentation Publication on website Other publication Submission to regulatory authorities Study data will be shared via ct.gov and other websites per regulations Data will be shared in future conferences and publications |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are not expected to be made available due to there being no requirement to do so. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
10/10/2023: The principal investigator confirmed that recruitment was ongoing.
05/09/2022: Internal review.
11/05/2022: Trial's existence confirmed by NHS HRA.
