Study Comparing Bemarituzumab plus Chemotherapy with Placebo and Chemotherapy in Previously Untreated Advanced Gastric or Gastroesophageal Junction Cancer with FGFR2b Overexpression (FORTITUDE-101)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Amgen Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

2 Feb 2022 → 26 Apr 2026

Decision date (initial)

2024-03-11

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Amgen Inc.

External identifiers

EU CT number

2023-505457-40-00

EudraCT number

2021-003461-35

WHO UTN

U1111-1299-3326

ClinicalTrials.gov

NCT05052801

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To compare efficacy of bemarituzumab plus mFOLFOX6 to placebo plus mFOLFOX6 as assessed by overall survival (OS) in subjects with FGFR2b ≥ 10% 2+/3+ tumor cell staining (FGFR2b ≥ 10% 2+/3+ TC)

Secondary objectives 8

1. To compare efficacy between the treatment arms as assessed by progression-free survival (PFS) in FGFR2b ≥ 10% 2+/3+ TC subjects
2. To compare efficacy between the treatment arms as assessed by objective response (OR) in FGFR2b ≥ 10% 2+/3+ TC subjects
3. To evaluate the safety and tolerability of bemarituzumab plus mFOLFOX6 compared to placebo plus mFOLFOX6
4. To compare efficacy of bemarituzumab plus mFOLFOX6 to placebo plus mFOLFOX6 in all randomized subjects as assessed by: OS PFS OR
5. To compare efficacy between treatment arms in FGFR2b ≥ 10% 2+/3+ TC subjects as assessed by:  duration of response (DOR)  disease control
6. To assess patient reported outcomes and Quality of Life (QoL) outcomes in FGFR2b ≥ 10% 2+/3+ TC subjects
7. To characterize the pharmacokinetics (PK) of bemarituzumab in combination with mFOLFOX6
8. To characterize the immunogenicity of bemarituzumab

Conditions and MedDRA coding

Previously Untreated Advanced Gastric or Gastroesophageal Junction Cancer with FGFR2b overexpression

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Swedish Medical Products Agency, Medicines Evaluation Board

Plan to share IPD

Yes

IPD plan description

De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Subject has provided informed consent prior to initiation of any study specific activities/procedures.
2. Age ≥18 years (or legal adult age within country, whichever is older)
3. Histologically documented gastric or GEJ adenocarcinoma (not amenable to curative therapy). Primary tumor location will be classified following the American Joint Committee on Cancer/Union for International Cancer Control [AJCC/UICC] 8th edition.
4. Disease that is unresectable, locally advanced, or metastatic (not amenable to curative therapy)
5. FGFR2b ≥ 10% 2+/3+ TC as determined by centrally performed IHC testing, based on tumor sample
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
7. Adequate organ function as follows: absolute neutrophil count ≥ 1.5 x 109/L platelet count ≥ 100 x 109/L hemoglobin ≥ 9 g/dL without red blood cell (RBC) transfusion within 7 days prior to the first dose of study treatment aspartate aminotransferase and ALT < 3x upper limit of normal (ULN) (or < 5 x ULN if liver involvement). Total bilirubin < 1.5 x ULN (or < 2 x ULN if liver involvement; with the exception of subjects with Gilbert's disease) calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/minute calculated using the formula of Cockcroft and Gault ([140 - Age]) x Mass [kg]/[72 x Creatinine mg/dL]) (x 0.85 if female) international normalized ratio or prothrombin time (PT) < 1.5 x ULN except for subjects receiving anticoagulation, who must be on a stable dose of anticoagulant therapy for 6 weeks prior to enrollment
8. Measurable disease or non-measurable, but evaluable disease, according to RECIST v1.1.
9. Subject has no contraindications to mFOLFOX6 chemotherapy

Exclusion criteria 25

1. Untreated or symptomatic central nervous system (CNS) metastases and leptomeningeal disease Subjects with asymptomatic CNS metastases are eligible if clinically stable for at least 4 weeks and do not require intervention (including use of corticosteroids). Subjects with treated brain metastases are eligible provided the following criteria are met: Definitive therapy was completed at least 2 weeks prior to the first planned dose of study treatment (stereotactic radiosurgery at least 7 days prior to first planned dose of study treatment) At least 7 days prior to first dose of study treatment: any CNS disease is clinically stable, subject is off steroids for CNS disease (unless steroids are indicated for a reason unrelated to CNS disease), and subject is off or on stable doses of anti-epileptic drugs
2. Unwillingness to avoid use of contact lenses during study treatment
3. Major surgical procedure within 28 days prior to first dose of study treatment
4. Impaired cardiac function or clinically significant cardiac disease including: unstable angina within 6 months prior to first dose of study treatment, acute myocardial infarction < 6 months prior to first dose of study treatment, New York Heart Association (NYHA) class II-IV congestive heart failure, uncontrolled hypertension (defined as an average systolic blood pressure > 160 mmHg or diastolic > 100 mm Hg despite optimal treatment (measured following European Society for Hypertension/European Society of Cardiology [ESH/ESC] 2018 guidelines); uncontrolled cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin, active coronary artery disease, QTc ≥ 470 msec
5. Peripheral sensory neuropathy G2 or higher
6. Active infection requiring systemic treatment or any uncontrolled infection ≤14 days prior to first dose of study treatment
7. Known positive HER2 status (as defined by positive IHC test of 3+ or IHC 2+ with positive in situ hybridization [ISH])
8. Known human immunodeficiency virus (HIV) infection with CD4+ T-cell (CD4+) counts < 350 cells/µL, hepatitis C infection (subjects with hepatitis C that achieve a sustained virologic response following antiviral therapy are allowed), or hepatitis B infection (subjects with hepatitis B surface antigen [SAg] or core antibody that achieve sustained virologic response with antiviral therapy directed at hepatitis B are allowed)
9. History of interstitial lung disease
10. History or evidence of systemic disease or ophthalmological disorders requiring chronic use of ophthalmic corticosteroids
11. Evidence of any ongoing ophthalmologic abnormalities or symptoms that are acute (within 4 weeks) or actively progressing
12. History of other malignancy within the past 2 years, except: curatively treated non-melanoma skin malignancy cervical cancer in situ curatively treated uterine cancer stage I curatively treated ductal or lobular breast carcinoma in situ and not currently receiving any systemic therapy localized prostate cancer that has been treated surgically with curative intent and presumed cured
13. Evidence of, or recent (within 6 months) history of, corneal defects, corneal ulcerations, keratitis, or keratoconus, history of corneal transplant, or other known abnormalities of the cornea that may pose an increased risk of developing a corneal ulcer. Recent (within 6 months) corneal surgery or ophthalmic laser treatment
14. Prior treatment for metastatic or unresectable disease except for a maximum of 1 dose of mFOLFOX6 Prior adjuvant, neo-adjuvant, and peri-operative therapy is allowed, if completed more than 6 months prior to the first dose of study treatment Palliative radiotherapy is allowed, provided it has been completed more than 14 days prior to the first dose of study treatment All treatment-related toxicity needs to be resolved to grade ≤ 1 prior to the first dose of study treatment, with the exception of alopecia or toxicities considered irreversible (defined as having been present and stable for > 21 days) which are not otherwise described in the exclusion criteria
15. Prior treatment with any selective inhibitor of the FGF-FGFR pathway
16. Currently receiving treatment in another investigational device or drug study, or within 28 days of first dose of study treatment or during this clinical study. Other investigational procedures while participating in this study are excluded
17. Female subjects of childbearing potential unwilling to use protocol specified method of contraception during treatment and for an additional 9 months after the last dose of protocol-mandated therapy
18. Female subjects who are breastfeeding or plan to breastfeed while on study through 3 months after the last dose of protocol-mandated therapy
19. Female subjects planning to become pregnant while on study through 9 months after the last dose of protocol-mandated therapy
20. Female subjects of childbearing potential with a positive pregnancy test assessed at screening and within 72 hours prior to first dose of study treatment
21. Male subjects with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use contraception during treatment and for an additional 6 months after the last dose of protocol-mandated therapy.
22. Male subjects unwilling to abstain from donating sperm during treatment and for an additional 6 months after the last dose of protocol-mandated therapy
23. Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures within the subject's capacity to the best of the subject and investigator’s knowledge
24. History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion
25. Known allergy, hypersensitivity, or contraindication to components of the bemarituzumab formulation including polysorbate

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall survival, defined as time from randomization until death from any cause. Subjects still alive will be censored at the date last known to be alive.

Secondary endpoints 18

1. Objective response, defined as best overall response (BOR) of complete response (CR) or partial response (PR) as determined by investigator per RECIST v1.1.
2. Treatment-emergent adverse events (including all adverse events, grade ≥3, serious adverse events, fatal adverse events, and adverse events requiring permanent discontinuation of investigational product)
3. Clinically significant changes in vital signs, visual acuity, and clinical laboratory tests
4. Overall survival in all randomized subjects
5. Progression-free survival in all randomized subjects
6. Objective response rate in all randomized subjects
7. Disease control defined as CR + PR + stable disease (SD).
8. Subjective score and change from baseline in following assessments:
9. European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) individual scores (raw and transformed) for the 5 functional scales, 9 symptom scales, global health status/quality of life scale, and change from baseline at each assessment
10. Stomach cancer related symptoms measured by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Stomach (EORTC-QLQ-STO22)
11. Summary scores at each assessment and changes from baseline of visual analogue scale (VAS) as measured by the EuroQol 5-dimensional (EQ-5D-5L)
12. Time to deterioration in stomach-cancer related symptoms scores
13. Time to deterioration in HRQoL scores
14. Time to deterioration in physical function scores
15. PK parameters for bemarituzumab, including maximum observed concentration (Cmax) and observed concentration at the end of a dose interval (Ctrough)
16. Anti-bemarituzumab antibody formation
17. DOR is defined as the time from the first documentation of OR (by investigator per RECIST v1.1) until the first documentation of disease progression or death due to any cause, whichever occurs first. Only subjects who have achieved OR will be evaluated for DOR. DOR will be censored at the last evaluable postbaseline tumor assessment prior to subsequent anticancer therapy; otherwise, at date of first documentation of objecvtive response.
18. PFS, defined as the time from randomization until the first documentation of radiologic disease progression or death due to any cause, whichever occurs first in the absence of subsequent anticancer therapy. PFS will be censored at the last evaluable post-baseline tumor assessment prior to subsequent anticancer therapy; otherwise, at randomization. Progression will be based on assessment by investigator per RECIST v1.1.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Auxiliary 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Amgen Inc.

Sponsor organisation

Amgen Inc.

Address

1 Amgen Center Drive

City

Thousand Oaks

Postcode

91320-1799

Country

United States

Scientific contact point

Organisation

Amgen Inc.

Contact name

Medical Information

Public contact point

Organisation

Amgen Inc.

Contact name

Medical Information

Third parties 11

Locations

18 EU/EEA countries · 103 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 2 · Art. 52 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 197 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications