Binimetinib in Patients With BRAF Fusion-positive Low-grade Glioma or Pancreatic Cancer (Perfume) (Perfume)

Phase II Investigator-initiated Trial of Binimetinib in Patients With BRAF Fusion-positive Low-grade Glioma or Pancreatic Cancer (Perfume)

This study is an open-label, parallel, 2-cohort, multicenter, investigator-initiated Phase 2 trial to evaluate the efficacy and safety of binimetinib in patients with advanced or recurrent low-grade glioma or pancreatic cancer harboring BRAF fusion/rearrangement.

Study Overview

• Status: Recruiting
• Conditions: Pancreatic Cancer; Low-grade Glioma
• Intervention / Treatment: Drug: Binimetinib 15 MG

Detailed Description

This study is an open-label, parallel, 2-cohort, multicenter, investigator-initiated Phase 2 trial. Eligible patients are with recurrent low-grade glioma (grade 1 and grade 2 tumors according to WHO classification) or advanced or recurrent pancreatic cancer harboring BRAF fusion/rearrangement. Patients receive binimetinib 45mg administered orally, twice daily.

Analyses will be performed on each of the two cohorts:

Cohort A: low-grade glioma Cohort B: pancreatic cancer

• Study Type: Interventional
• Enrollment (Estimated): 32
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Chigusa Morizane, M.D., Ph.D.; Phone Number: 0335422511; Email: ncch2101_office@ml.res.ncc.go.jp
• Study Contact Backup: Name: Tomoyuki Satake, M.D., Ph.D.; Email: ncch2101_office@ml.res.ncc.go.jp

Study Locations

• Japan
  • Fukuoka, Japan, 812-8582
    • Recruiting
    • Kyushu University Hospital
    • Contact: Kenji Tsuchihashi, M.D., Ph.D.
  • Chiba
    • Kashiwa, Chiba, Japan, 277-8577
      • Recruiting
      • National Cancer Center Hospital East
      • Contact: Tomoyuki Satake, M.D.
  • Hokkaido
    • Sapporo, Hokkaido, Japan, 060-8648
      • Recruiting
      • Hokkaido University Hospital
      • Contact: Ichiro Kinoshita, M.D., Ph.D.
  • Kyoto
    • Kyoto City, Kyoto, Japan, 606-8507
      • Recruiting
      • Kyoto University Hospital
      • Contact: Masafumi Kanai, M.D., Ph.D.
  • Miyagi
    • Sendai, Miyagi, Japan, 980-8574
      • Recruiting
      • Tohoku University Hospital
      • Contact: Keigo Komine, M.D., Ph.D.
  • Tokyo
    • Chuo-ku, Tokyo, Japan, 104-0045
      • Recruiting
      • National Cancer Center Japan
      • Contact: Chigusa Morizane, M.D., Ph.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Inclusion criteria for both cohort A and B

1. BRAF fusion or rearrangement is detected by reimbursed NGS-based cancer gene panel tests, cancer gene panel tests performed under advanced medical treatment, or clinical study (including liquid biopsy).
2. Unresectable or recurrent
3. No symptomatic brain metastasis, carcinomatous meningitis or spinal metastasis requiring surgical intervention or radiotherapy
4. No cardiac effusion, pleural effusion, or ascites requiring treatment
5. Not received anti-cancer drug within 14 days before registration, nor received other study drug (molecular targeting drug, immune therapy) within 21 days before registration
6. Not received operation under general anesthesia within 28 days before registration
7. Not received radiation therapy (including gamma knife, cyber knife) within 14 days before registration
8. Left ventricular ejection fraction >= 50% by echocardiography or MUGA (multigated acquisition scan) within 28 days before registration
9. Having all laboratory tests performed within 14 days before registration and the values are within the following range. Patients should not receive administration of G-CSF and/or blood transfusion within 14 days before the blood collection (1) Absolute neutrophil count >= 1.500/mm3 (2) Platelet count >= 10.0 X 10(4))/mm3 (3) Hemoglobin >= 8.0 g/dL (4) Total bilirubin <= 1.5 g/dL (5) Aspartate aminotransferase (AST) <= 100 U/L (6) Alanine aminotransferase (ALT) <= 100 U/L (7) Serum creatinine <= 1.5 mg/dL
10. Patients who are able to swallow orally administered medication.
11. Consent to at least 30 days of contraception and limited egg donation (including egg retrieval for future egg transfer) after last administration of study drug for child-bearing status women. Consent to 90 days of contraception and limited sperm donation after last administration of study drug for men.

12. Written informed consent (When registering patient under 18, a signed consent form must be obtained from both the patient and the parent or legal guardian.)

    Cohort A

13. Histopathologically diagnosed as low-grade glioma, based on WHO classification of 2007, 2016 and 2021. The grade is WHO grade 1 or 2.
14. Age at the time of registration is 12 years or older (When registering a patient under 18, a signed consent form must be obtained from both the patient and the parent or legal guardian), and patients who are 12-17 years old have to be 40 kg or over in body weight. There is no limitation in body weight for patients who are 18 years or older.
15. Lansky Performance Status (LPS) >= 70 for patients 12-15 years old Karnofsky Performance Status (KPS) >= 70 for patients 16 years or older
16. Having measurable disease within 28 days before registration
17. Patients suffice the following. (1) Having adequate initial treatment depending on the primary central nervous tumor including surgery if recommended treatment is available. (2) Neurologically stable.

(3) Multiple lesion or dissemination is not detected with MRI at the registration.

18) Not increased steroid for low-grade glioma within 14 days before registration and the dosage of steroid in equivalent to 50 mg prednisolone or less.

Cohort B 19) Histopathologically diagnosed as pancreatic cancer (histologically not specified).

20) Having progression after at least one regimen of chemotherapy excluding adjuvant therapy.

21) Age at the time of registration is 18 years or older. 22) Performance Status (ECOG) is 0 or 1 23) Having measurable disease within 28 days before registration detected by enhanced CT (Head, chest, abdominal, pelvic: under 5 mm in slice)

Exclusion Criteria:

1. Active double primary cancer (but not [1]-[3]): [1] completely resected following cancers: basal cell carcinoma, stage I squamous cell carcinoma, carcinoma in situ, intramucosal carcinoma, superficial bladder cancer, [2] gastrointestinal cancer curatively resected with ESD or EMR, and [3] other cancers with no recurrence for more than 5 years.
2. Patients with symptomatic congestive heart failure of NYHA class II-IV or arrythmia (over grade 2) occurring in less than 6 months before registration.
3. Patients with myocardial infarction or unstable angina occurring in less than 6 months before registration.
4. Patients with corrected QT interval (QTcF) > 480 ms in ECG performed within 14 days before enrollment.
5. Patients with infections requiring systemic treatment.
6. Patients with uncontrolled hypertension (systolic blood pressure: over 150 mmHg or diastolic blood pressure: over 100 mmHg).
7. Patients with history or findings of retinal vein occlusion (RVO) or having RVO risk factor (unstable glaucoma, ocular hypertension, hyperviscosity syndrome, hypercoagulability syndrome, etc.)
8. Patients with history or complication of retinal degenerative disease other than RVO (central serous chorioretinopathy, retinal detachment, age-related macular degeneration, etc.)
9. Patients with uncontrolled diabetes mellitis.
10. Patients with venous thrombus (transient ischemic attack, stroke, massive deep vein thrombosis, pulmonary embolism, etc.) occurring in less than 3 months
11. Patients who have neuromuscular disease with CK elevation (inflammatory myopathy, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy, etc.).
12. Prior treatment with MEK inhibitors.
13. Previous severe hypersensitive reaction to ingredient including binimetinib.
14. Patients who are positive for either HIV antibody, HBs antigen, or HCV-RNA.
15. Negative for HBs antigen, positive for HBs antibody or HBc antibody, and positive for HBV-DNA assay. (If it is less than or equal to the detection sensitivity, patients are not excluded)
16. Patients with concomitant diseases that affect gastrointestinal function.
17. Women who are pregnant, breastfeeding and need to continue breastfeeding in the future, and women who may be pregnant.
18. Patients with psychiatric diseases or psychological symptoms interfering with participation in the trial.
19. Patients who are deemed inappropriate for participation in the trial by the principal investigator or sub-investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Binimetinib	Drug: Binimetinib 15 MG; Binimetinib 45mg is orally administered twice daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (centrally assessed)	Overall response rate (ORR) defined as the combined incidence of complete response (CR) and PR, within cohort A FAS, cohort B FAS, and confirmed no less than 4 weeks after the criteria for response are first met, based on RECIST v1.1. ORR will be confirmed by independent blinded central review assessment.	Baseline up to 4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (investigator assessed by RECIST)	Overall response rate (ORR) defined as the combined incidence of complete response (CR) and PR, within cohort A FAS, cohort B FAS, and confirmed no less than 4 weeks after the criteria for response are first met, based on RECIST v1.1. ORR will be performed by investigator assessment.	Baseline up to 4 years
Overall response rate (investigator assessed by RANO)	Overall response rate (ORR) defined as the combined incidence of complete response (CR) and PR, within cohort A FAS, and confirmed no less than 4 weeks after the criteria for response are first met, based on Response Assessment in Neuro-Oncology (RANO) criteria. ORR will be confirmed by local site investigator assessment.	Baseline up to 4 years
Overall response rate including minor response(investigator assessed by RANO)	Overall response rate (ORR) defined as the combined incidence of complete response (CR) PR and SD, within cohort A FAS, and confirmed no less than 4 weeks after the criteria for response are first met, based on Response Assessment in Neuro-Oncology (RANO) criteria. ORR will be confirmed by local site investigator assessment.	Baseline up to 4 years
Progression-free survival	Progression-free survival (PFS) defined as the time from the date of enrollment to the date of the first documentation of objective progression of disease (PD), clinically diagnosed symptomatic deterioration, or death due to any cause in the absence of documented PD, whichever occurs first within cohort A FAS and cohort B FAS.	Baseline up to 4 years
Overall survival	Overall survival (OS) defined as the time from date of enrollment to date of death due to any cause within cohort A FAS and cohort B FAS.	Baseline up to 4 years
Disease control rate	Disease control rate (DCR) defined as the percentage of patients with a confirmed complete response (CR), partial response (PR) or stable disease (SD) as the best overall according to RECIST version 1.1 within cohort A FAS and cohort B FAS.	Baseline up to 4 years
Duration of response	Duration of Response (DOR) defined as the time from the date of first documentation of CR or PR to the date of first documentation of disease progression or date of death from any cause, whichever occurs first within cohort A FAS and cohort B FAS.	Baseline up to 4 years
Adverse event rate	Defined as the percentage of patients who experienced each adverse event. The severity of AEs were evaluated by the investigator according to Japan Clinical Oncology Group (JCOG) Japanese translation of the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0-JCOG) within cohort A FAS and cohort B FAS.	Baseline up to 4 years

Collaborators and Investigators

• Sponsor: National Cancer Center, Japan
• Collaborators: Ono Pharmaceutical Co. Ltd

Study record dates

Study Major Dates

• Study Start (Actual): March 29, 2023
• Primary Completion (Estimated): February 28, 2027
• Study Completion (Estimated): September 30, 2027

Study Registration Dates

• First Submitted: November 28, 2023
• First Submitted That Met QC Criteria: November 28, 2023
• First Posted (Actual): December 6, 2023

Study Record Updates

• Last Update Posted (Estimated): December 13, 2023
• Last Update Submitted That Met QC Criteria: December 6, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: BRAF fusion; BRAF rearrangement; Binimetinib
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Pancreatic Diseases; Glioma; Pancreatic Neoplasms
• Other Study ID Numbers: NCCH2101/MK011

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No