IRB Study Number 26-333
Status Recruiting
Phase Phase 1
Location Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
ENROLLING BLADDER ONLY
This is a multicenter, open-label, dose-escalation, dose expansion and dose confirmation study to evaluate safety, tolerability, PK, immunogenicity, pharmacodynamics and antitumor activity.
This trial will enroll adult participants with urothelial cancer of the urinary tract: (including renal pelvis, ureters, urinary bladder, and urethra), non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC) regardless of the presence of an activating FGFR3 alteration (mutation, fusion, or amplification) or high FGFR3 protein or mRNA expression in the absence of a detectable genetic alteration.
In the Dose-escalation, Dose-expansion Cohorts, and Dose Confirmation Cohorts, other adult participants with an advanced or metastatic cancer with a documented activating FGFR3 alteration (mutation, fusion, or amplification) or high FGFR3 protein or mRNA expression in the absence of a detectable genetic alteration will also be eligible to enroll.
All participants must have progressed following or are intolerant of standard-of-care therapy or for which no standard therapy is available.
Inclusion Criteria
ENROLLING BLADDER ONLY
To be eligible to participate in this study, candidates must meet all the following inclusion criteria and none of the following exclusion criteria:
Written informed consent must be obtained from the participant in accordance with requirements of the study center’s institutional review board (IRB) or ethics committee, prior to the initiation of any protocol-required procedures
Age ≥ 18 years (or age ≥ 19 years as the age of majority as required by local regulation)
Participants consent to provide tumor tissue collected prior to study treatment, preferably from a biopsy performed after their last anticancer therapy and within 90 days of the start of study treatment. An older archival sample may be acceptable with Sponsor approval
Participants must have progressed following, are intolerant of, or have no available standard-of-care therapy
Participants with histologically or cytologically confirmed locally advanced/metastatic relapsed or refractory solid tumors as outlined below:
a. Dose-escalation and Dose-expansion (Backfill) Cohorts:
o Participants with urothelial cancer of the urinary tract: (including renal pelvis, ureters, urinary bladder, and urethra), non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC) regardless of the presence of an activating FGFR3 alteration (mutation, fusion, or amplification) or high FGFR3 protein or mRNA expression in the absence of a detectable genetic alteration.
o Other advanced or metastatic solid tumors with a documented activating FGFR3 alteration (mutation, fusion, or amplification) or high FGFR3 protein or mRNA expression in the absence of a detectable genetic alteration.
b. Dose Confirmation Cohort:
o Participants with urothelial cancer of the urinary tract: (including renal pelvis, ureters, urinary bladder, and urethra), non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC) regardless of the presence of an activating FGFR3 alteration (mutation, fusion, or amplification) or high FGFR3 protein or mRNA expression in the absence of a detectable genetic alteration.
o Other advanced or metastatic solid tumors with a documented activating FGFR3 alteration (mutation, fusion, or amplification) or high FGFR3 protein or mRNA expression in the absence of a detectable genetic alteration, as determined by a validated assay performed in a CLIA certified local or central laboratory.
Measurable disease per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria
Participants must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Acceptable liver function:
a. Bilirubin ≤ 1.5 × upper limit of normal (ULN); participants with known Gilbert’s syndrome who have total bilirubin level ≤3×ULN may be enrolled
b. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase ≤ 2.5 × ULN (if liver metastases are present, then ≤ 5 × ULN is allowed)
Acceptable renal function:
a. Serum creatinine ≤1.5 × ULN, or creatinine clearance ≥50 mL/min as calculated using the modified Cockcroft-Gault equation; confirmation of creatinine clearance is only required when creatinine is >1.5 × ULN; 24-hour urine collection is allowed, but not required
Acceptable hematologic status: Blood transfusion or growth factor support is not allowed within 7 days prior to blood samples that will be used to establish eligibility
a. Absolute neutrophil count ≥ 1500 /mm3; participants with known Duffy null phenotype who have absolute neutrophil count ≥ 1,200/mm3 may be enrolled
b. Platelet count ≥ 100,000 /mm3
c. Hemoglobin ≥ 9 g/dL
d. Activated partial thromboplastin time (aPTT) ≤1.5×ULN. Study participants on therapeutic doses of anticoagulation medication must have INR and/or aPTT ≤ the upper limit of the therapeutic range for intended use
A negative urine or serum pregnancy test (if a woman of childbearing potential)
Women of childbearing potential and men must agree to use adequate contraception (see Section 5.9) prior to study entry, for the duration of study participation and for 7 months (for women) or 4 months (for men) after the last dose of study drug
Exclusion Criteria
To be eligible for entry into the study, the participant must not meet any of the exclusion criteria listed below:
Prior treatment with antibody drug conjugate (ADC) with a topoisomerase inhibitor payload. Prior direct treatment with topoisomerase inhibitors (e.g., irinotecan, topotecan, belotecan, nano-liposomal irinotecan) are not exclusionary
Participant has clinically significant intercurrent disease including, but not limited to:
New York Heart Association Class III or IV heart failure
Myocardial infarction, unstable angina, or stroke ≤6 months prior to C1D1
Newly diagnosed thromboembolic events that require therapeutic intervention over the last 6 months prior to C1D1 (participants with stable control of lower limb deep venous thrombosis over at least 3 months are allowed)
Severe aortic stenosis
Uncontrolled arrhythmia
Symptomatic pericardial effusion
Congenital long QT syndrome
A mean of Fredericia’s formula-QT corrected interval (QTcF) prolongation to >470 msec based on a 12-lead ECG
Uncontrolled hypertension (systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥110 mmHg) or diabetes (hemoglobin A1C ≥9.0%)
Left ventricular ejection fraction (LVEF) <45% determined by echocardiogram or multiple gated acquisition scan (MUGA)
Symptomatic pleural effusion (<90% oxygen saturation)
Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy
Primary central nervous system (CNS) tumors, current or previously treated leptomeningeal disease or known active brain metastases
NOTE: Participants with previously treated clinically stable, radiologically stable brain metastases maybe eligible
Pregnant or nursing women
Any standard cancer therapy (e.g., chemotherapy, hormonal therapy, radiotherapy, immunotherapy, biologic therapy treatment) or experimental therapy within 4 weeks or 5 half-lives, whichever is shorter, prior to C1D1. The interval may be reduced to 2 weeks for bone-only radiation therapy. Any major surgical procedure within 6 weeks prior to C1D1
Concomitant use of OATP1B1 and OATP1B3 inhibitors that are known to increase exposure for sensitive substrate drugs by ≥2-fold within 14 days prior to starting study drug and throughout the trial. See Section 20.5 for a list of OATP1B1 and OATP1B3 inhibitors
Participants have not recovered (i.e., improvement to Grade 1 or better) from all acute toxicities from previous therapy, excluding alopecia and vitiligo. If the participant has an ongoing, stable, chronic Grade 2 toxicity they may be eligible after discussion with Sponsor on a case-by-case basis
Any clinically significant corneal or retinal abnormality that may increase the risk of eye toxicity
Known active infection with human immunodeficiency virus (HIV), human T-cell leukemia virus, type 1 (HTLV-1), hepatitis B virus (HBV), or hepatitis C virus (HCV), if allowed by local regulations
a. Participants with hepatitis B (hepatitis B virus surface antigen [HbsAg] positive), or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV ribonucleic acid). Participants with HCV with undetectable virus after treatment are eligible. Participants with a prior history of hepatitis B virus are eligible if quantitative polymerase change reaction for hepatitis B virus DNA is negative
b. Participants with human immunodeficiency virus (HIV) infection with acquired immune deficiency syndrome (AIDS) defining illness are not eligible for enrollment; however, participants who have had HIV infection and who have a cluster of differentiation 4 (CD4) + T cell count >350 cells/μL and no history of an AIDS-defining illness are eligible for entry
Has an active second malignancy. Note: participants with a history of malignancy that have been completely treated, with no evidence of active cancer for 3 years prior to enrolment, or participants with tumors cured with radiotherapy or surgery with low risk of recurrence (e.g., nonmelanoma skin cancer, histologically confirmed complete excision of carcinoma in situ) are allowed
Participants who in the opinion of the Investigator will not be able to adhere to the schedule of assessments and/or may have difficulties complying with the treatment regimen or are unwilling or unable to comply with procedures required in this protocol
Known sensitivity to BHV-1530 or any of the excipients in BHV-1530
History of (noninfectious) clinically significant interstitial lung disease (ILD)/pneumonitis that required steroids, active clinically significant ILD/pneumonitis, or suspected clinically significant ILD/pneumonitis that cannot be ruled out by imaging at screening
Requires supplemental oxygen for daily activities
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment
