A Study of Bemarituzumab (FPA144) Combined With Modified FOLFOX6 in Gastric/Gastroesophageal Cancer

Phase 1 is an open-label dose-escalation of bemarituzumab in combination with modified FOLFOX6 (mFOLFOX6). Eligible patients will have unresectable locally advanced or metastatic GI cancer of any type and be candidates to receive at least 2 doses of mFOLFOX6 chemotherapy. Phase 1 consists of 2 dosing cohorts of bemarituzumab in combination with mFOLFOX6 to determine the recommended dose of bemarituzumab in combination with mFOLFOX6 for the phase 2 portion of the study (see study record NCT03694522).

• Bemarituzumab (Biological), also known as FPA144: Administered by intravenous infusion over approximately 30 minutes
• Modified FOLFOX6 (Drug), also known as mFOLFOX6: Modified FOLFOX6 regimen consists of the following: * Oxaliplatin 85 mg/m² IV infusion over 120 minutes * Leucovorin 400 mg/m² IV infusion over 120 minutes, or 200 mg/m² levo-leucovorin if leucovorin is unavailable * 5-fluorouracil (5-FU) 400 mg/m² bolus over approximately 5 minutes then 5-FU 2400 mg/m² as a continuous IV infusion over approximately 48 hours.

Primary outcomes

• Number of Participants With Treatment-related Adverse Events ≥ Grade 2 [From first dose of study drug up to 28 days after last dose; Actual median (min, max) duration of treatment emergent period was 19.3 (12.3, 22.3) weeks in the bemarituzumab 6 mg/kg group and 19.4 (4.0, 35.4) weeks in the bemarituzumab 15 mg/kg group.]: A treatment-related adverse event (TRAE) is defined as an adverse event (AE) with an onset date on or after the date of first dose of study treatment, or an event present before treatment that worsened after treatment, and with an onset date prior to 28 days after the last date of dose, for which the investigator assessed as related to investigational product The investigator classified the severity of each AE using the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 5.0 on a scale from mild (Grade 1), moderate (Grade 2), severe (Grade 3), life-threatening (Grade 4), or death due to the AE (Grade 5).
• Number of Participants With Dose Limiting Toxicities (DLTs) [28 days]: DLTs were defined as any of the following events considered by the investigator to be related to study drug: * Absolute neutrophil count (ANC) < 0.5 × 10⁹/L > 5 days duration or febrile neutropenia. * Platelets < 25 × 10⁹/L or < 50 × 10⁹/L with bleeding requiring medical intervention or for > 3 days. * Grade 4 anemia. * Any Grade 2-3 ophthalmologic AE not resolving within 7 days. * Any Grade 4 ophthalmologic AE. * Any Grade 4 laboratory value. * Any Grade 3 laboratory values that are not of clinical significance according to investigator and Sponsor agreement if they do not resolve within 72 hours. * Aspartate aminotransferase/alanine aminotransferase (AST/ALT) ≥ 3× upper limit of normal (ULN) and concurrent total bilirubin ≥ 2× ULN not related to liver involvement with cancer. * Any non-hematological AE ≥ Grade 3 (except nausea, vomiting, and diarrhea). * Grade 3 nausea, vomiting or diarrhea not resolving with supportive care in 72 hours. * Grade 4 nausea, vomiting or diarrhea.

Secondary outcomes

• Number of Participants With Treatment-emergent Adverse Events [From first dose of study drug up to 28 days after last dose; Actual median (min, max) duration of the treatment emergent period was 19.3 (12.3, 22.3) weeks in the bemarituzumab 6 mg/kg group and 19.4 (4.0, 35.4) weeks in the bemarituzumab 15 mg/kg group.]: Treatment-emergent adverse events are defined as adverse events (AEs) that started or worsened between the start of study drug and 28 days after permanent discontinuation of study drug. A serious AE is defined as any untoward medical occurrence that at any dose: * Resulted in death; * Was life-threatening; * Required inpatient hospitalization or prolongation of existing hospitalization; * Resulted in persistent or significant disability or incapacity; * Was a congenital anomaly or birth defect. The investigator assessed the causality/relationship between the study treatment and each AE, and assessed the severity of each AE according to the guidelines provided in NCI-CTCAE, version 5.0 on a scale from mild (Grade 1), moderate (Grade 2), severe (Grade 3), life-threatening (Grade 4), or death due to the AE (Grade 5). Ocular events associated with symptomatic corneal involvement and symptomatic and asymptomatic retinal involvement were events of special interest in this study.
• Maximum Observed Serum Concentration (Cmax) of Bemarituzumab [Cycle 1 day 1 at predose, 0.25, 4, 48, and 168 hours after end of infusion, and for participants in Cohort 2 day 8 at 0.25 and 4 hours end of infusion; Cycle 2 day 1 at predose, 0.25 and 48 hours after end of infusion.]
• Observed Serum Concentration of Bemarituzumab at the End of the Dose Interval (Ctrough) [Cycle 1 day 14 predose for cohort 1 and day 8 predose for cohort 2; Cycle 2 day 14 predose]
• Area Under the Observed Concentration-time Curve From the Time of Dosing to Day 14 (AUC0-14) [Cycle 1 day 1 at predose, 0.25, 4, 48, and 168 hours after end of infusion, and for participants in Cohort 2 day 8 at 0.25 and 4 hours after the end of infusion.]: Area under the observed concentration-time curve from the time of dosing to Day 14 (0-336h) calculated by log-linear trapezoidal approximation.
• Terminal Half-life (t1/2) of Bemarituzumab [Cycle 1 day 1 at predose, 0.25, 4, 48, and 168 hours after end of infusion, and for participants in Cohort 2 day 8 at 0.25 and 4 hours after end of infusion.]
• Number of Participants With Treatment Induced Anti-bemarituzumab Antibodies [Samples were collected for ADA analysis predose on day 1 of Cycles 1, 2, 3, 7, and 10 and at 28 days following the last dose.]: Postbaseline treatment induced antidrug antibody (ADA) positive is defined as participants with * ADA negative at baseline and ADA positive at any postbaseline timepoint, or * ADA positive at baseline and ADA positive with titer of at least 4-fold of the baseline titer at one or more postbaseline timepoint.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Disease that is unresectable, locally advanced, or metastatic (not amendable to curative therapy)
2. Understand and sign an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved informed consent form (ICF) prior to any study-specific evaluation
3. Life expectancy of at least 3 months in the opinion of the investigator
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
5. Age ≥ 18 years at the time the ICF is signed
6. In sexually active patients (women of childbearing potential and males), willingness to use 2 effective methods of contraception, of which 1 must be a physical barrier method (condom, diaphragm, or cervical/vault cap) until 6 months after the last dose of FPA144. Other effective forms of contraception include:

   * Permanent sterilization (hysterectomy and/or bilateral oophorectomy, or bilateral tubal ligation with surgery, or vasectomy) at least 6 months prior to Screening
   * Women of childbearing potential who are on stable oral contraceptive therapy or intrauterine or implant device for at least 90 days prior to the study, or abstain from sexual intercourse as a way of living
7. Adequate hematological and biological function, confirmed by the following laboratory values within 96 hours prior to enrollment:

   Bone Marrow Function
   * Absolute neutrophil count (ANC) ≥ 1.5 × 10\^9/L
   * Platelets ≥ 100 × 10\^9/L
   * Hemoglobin ≥ 9 g/dL

   Hepatic Function
   * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 × upper limit of normal (ULN); if liver metastases, then < 5 × ULN
   * Bilirubin < 1.5 × ULN except in patients with Gilbert's disease

   Renal Function
   * Calculated creatinine clearance using cockcroft Gault formula ≥ 50 mL/min or estimated glomerular filtrate rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula ≥ 50 mL/min
8. International normalized ratio (INR) or prothrombin time (PT) < 1.5 x the ULN except for patients receiving anticoagulation, who must be on a stable dose of warfarin for 6 weeks prior to enrollment
9. Measurable or non-measurable, but evaluable disease using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
10. Histologically or cytologically confirmed GI malignancy for which mFOLFOX6 is considered an appropriate treatment (e.g., gastric cancer \[GC\], colorectal carcinoma, pancreatic adenocarcinoma)
11. Patient must be a candidate to receive at least 2 doses of mFOLFOX6 chemotherapy

Exclusion Criteria:

1. Untreated or symptomatic central nervous system (CNS) metastases (CNS imaging not required). Patients with asymptomatic CNS metastases are eligible provided they have been clinically stable for at least 4 weeks and do not require intervention such as surgery, radiation, or any corticosteroid therapy for management of symptoms related to CNS disease
2. Impaired cardiac function or clinically significant cardiac disease, including any of the following (Criteria a through g):

   1. Unstable angina pectoris ≤ 6 months prior to enrollment
   2. Acute myocardial infarction ≤ 6 months prior to enrollment
   3. New York Heart Association Class II-IV congestive heart failure
   4. Uncontrolled hypertension (as defined as ≥ 160/90 despite optimal medical management)
   5. Uncontrolled cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin
   6. Active coronary artery disease
   7. Fridericia's corrected QT interval (QTcF) ≥ 480
3. Peripheral sensory neuropathy ≥ Common Terminology Criteria for Adverse Events (CTCAE) Grade 2
4. Active infection requiring systemic treatment or any uncontrolled infection ≤ 14 days prior to enrollment
5. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, or known active or chronic hepatitis B or C infection
6. History of interstitial lung disease (e.g., pneumonitis or pulmonary fibrosis)
7. Evidence or history of bleeding diathesis or coagulopathy
8. Radiotherapy ≤ 28 days of enrollment. Patients must be recovered from all acute radiotherapy-related toxicities. No radiopharmaceuticals (strontium, samarium) within 8 weeks of enrollment
9. Prior treatment with any selective inhibitor (e.g., AZD4547, BGJ398, JNJ-42756493, BAY1179470) of the fibroblast growth factor (FGF)-FGFR pathway
10. Ongoing adverse effects from prior systemic treatment > CTCAE Grade 1 (with the exception of Grade 2 alopecia)
11. Participation in another therapeutic clinical study or receiving any investigational agent within 28 days of enrollment or during this clinical study
12. Corneal defects, corneal ulcerations, keratitis, keratoconus, history of corneal transplant, or other known abnormalities of the cornea that may pose an increased risk of developing a corneal ulcer
13. Known positivity for human epidermal growth factor receptor 2 (HER2) (as defined by a positive immunohistochemistry \[IHC\] test of 3+ or IHC of 2+ with fluorescent in situ hybridization \[FISH\])
14. Major surgical procedures not permitted ≤ 28 days prior to enrollment. Surgery requiring local/epidural anesthesia must be completed at least 72 hours before enrollment. In all cases the patient must be sufficiently recovered and stable before treatment administration
15. Women who are pregnant or breastfeeding (unless the patient is willing to interrupt breastfeeding during study treatment administration and then resume 6 months after study discontinuation); women of childbearing potential must not consider getting pregnant during the study
16. Presence of any serious or unstable concomitant systemic disorder incompatible with the clinical study (e.g., substance abuse, psychiatric disturbance, uncontrolled intercurrent illness including arterial thrombosis, or symptomatic pulmonary embolism)
17. Presence of any other condition that may increase the risk associated with study participation, or may interfere with the interpretation of study results, and, in the opinion of the investigator, would make the patient inappropriate for entry in the study
18. Known allergy, hypersensitivity or contraindication to components of the FPA144 formulation including polysorbate or to platinum-containing medications, 5-FU, or leucovorin
19. History of prior malignancy, except (Criteria a through f):

    1. Curatively treated non-melanoma skin malignancy
    2. Cervical cancer in situ
    3. Curatively treated Stage I uterine cancer
    4. Curatively treated ductal or lobular breast carcinoma in situ and not currently receiving any systemic therapy
    5. Localized prostate cancer that has been treated surgically with curative intent and presumed cured
    6. Solid tumor treated curatively more than 5 years previously without evidence of recurrence

Participant flow

Outcome results

• Number of Participants With Treatment-related Adverse Events ≥ Grade 2 (Primary), Count of participants, Participants: Bemarituzumab 6 mg/kg + mFOLFOX6 1; Bemarituzumab 15 mg/kg + mFOLFOX6 4
• Number of Participants With Dose Limiting Toxicities (DLTs) (Primary), Count of participants, Participants: Bemarituzumab 6 mg/kg + mFOLFOX6 0; Bemarituzumab 15 mg/kg + mFOLFOX6 0
• Number of Participants With Treatment-emergent Adverse Events (Secondary), Count of participants, Participants: Bemarituzumab 6 mg/kg + mFOLFOX6 3; Bemarituzumab 15 mg/kg + mFOLFOX6 9
• Maximum Observed Serum Concentration (Cmax) of Bemarituzumab (Secondary), Mean, µg/mL: Bemarituzumab 6 mg/kg + mFOLFOX6 119 +/- 8.52; Bemarituzumab 15 mg/kg + mFOLFOX6 329 +/- 60.3
• Observed Serum Concentration of Bemarituzumab at the End of the Dose Interval (Ctrough) (Secondary), Mean, µg/mL: Bemarituzumab 6 mg/kg + mFOLFOX6 16.5 +/- 8.80; Bemarituzumab 15 mg/kg + mFOLFOX6 118 +/- 25.1
• Area Under the Observed Concentration-time Curve From the Time of Dosing to Day 14 (AUC0-14) (Secondary), Mean, μg*day/mL: Bemarituzumab 6 mg/kg + mFOLFOX6 556 +/- 232; Bemarituzumab 15 mg/kg + mFOLFOX6 2350 +/- 394
• Terminal Half-life (t1/2) of Bemarituzumab (Secondary), Mean, days: Bemarituzumab 6 mg/kg + mFOLFOX6 8.35 +/- 3.36; Bemarituzumab 15 mg/kg + mFOLFOX6 4.23 +/- 0.447
• Number of Participants With Treatment Induced Anti-bemarituzumab Antibodies (Secondary), Count of participants, Participants: Bemarituzumab 6 mg/kg + mFOLFOX6 0; Bemarituzumab 15 mg/kg + mFOLFOX6 0

Adverse events

Time frame: All-cause mortality: From enrollment to end of study; median (min, max) time on study was 19.4 (13.9, 22.4) weeks in Bemarituzumab 6 mg/kg + mFOLFOX6 and 28.6 (4.3, 49.6) weeks in Bemarituzumab 15 mg/kg + mFOLFOX6 group. Adverse Events: From first dose of any study drug to 28 days after last dose; Actual median (min, max) duration of treatment emergent period was 19.3 (12.3, 22.3) weeks in Bemarituzumab 6 mg/kg + mFOLFOX6 and 19.4 (4.0, 35.4) weeks in Bemarituzumab 15 mg/kg + mFOLFOX6 group.

Serious adverse events by term

Other adverse events by term

26 more terms not shown.

• Study Protocol (PDF, 2021-03-10)
• Statistical Analysis Plan (PDF, 2020-10-20)

• MD, Study director, Amgen