Phase I/II Study of the Safety, Pharmacokinetics, and Preliminary Clinical Activity of BT5528 in Patients with Advanced Malignancies Associated with EphA2 Expressio
- Conditions
- Advanced Malignancies Associated with EphA2 ExpressionMedDRA version: 21.1Level: LLTClassification code 10065147Term: Malignant solid tumorSystem Organ Class: 100000004864Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2019-003653-29-GB
- Lead Sponsor
- Bicycle Tx Limited
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 166
1. Written informed consent; at least 18 years of age
2. ECOG Performance Status score of 0 or 1; measurable disease per RECIST v1.1
3. Acceptable organ function:
- Creatinine clearance =50 mL/min by Cockcroft-Gault equation or 24-hour urine collection
- Total bilirubin =1.5 × ULN
- Serum albumin =2.5 g/dL
- AST =2.5 × ULN or =5 × ULN in presence of liver metastases
- ALT =2.5 × ULN or =5 × ULN in presence of liver metastases
- INR <1.3 or = institutional ULN
4. Acceptable hematologic function (no red blood cell or platelet transfusions or growth factors allowed within 4 weeks of first dose of BT5528):
- Hemoglobin =9 g/dL
- ANC =1500 cells/mm3
- Platelet count =75,000 cells/mm3
5.Negative pregnancy test for women of childbearing potential. Male patients with female partners of childbearing potential and female patients of childbearing potential must follow highly effective contraception (oral and hormonal contraceptives allowed) at least as conservative as Clinical Trial Facilitation Group recommendations for less than 1% failure rate during participation in the study and for 6 months after last dose of study drug. Male patients must refrain from donating sperm during study participation and for 6 months after last dose of study drug and women must not breastfeed or donate eggs.
6. Availability of archived tumor samples or willingness to provide fresh tumor biopsy during screening for EphA2 assessment.
7. Life expectancy =12 weeks 10. Willing and able to comply with protocol and study procedures.
Additional Inclusion Criteria – Part A
1. Patients with metastatic recurrent histologically confirmed malignant solid tumor who must have exhausted all appropriate treatment options per local guidelines and must have failed at least one prior line of therapy with evidence of radiographic progression on the most recent line of therapy. If applicable, patients who received prior immunotherapy, the last dose must have been at least 28 days prior to the first dose of BT5528 study treatment. Patients with pancreatic cancer are allowable but are planned for less than 50% of total patients enrolled in each escalation cohort. The Sponsor or SRC may decide to require enrollment of specific tumor types or subtypes at any point during the escalation if it is felt necessary to enrich the evaluation of biomarkers, safety or PK in a specific tumor type.
2. Patients enrolling in Cohort 4 or later for the Part A-1 monotherapy, or enrolling in Cohort 3 or later for the Part A-2 combination therapy, must have tumor tissue (fresh or archived) submitted to central laboratory with confirmation of positive EphA2 tumor expression prior to initiating study treatment. Patients with ovarian cancer enrolling in Cohort 4 or later for the Part A-1 monotherapy, or enrolling in Cohort 3 or later for the Part A-2 combination therapy may be enrolled without prior confirmation of EphA2 expression. The SRC may review the requirement for EphA2 expression prior to starting therapy where individual tumor types or subtypes have already demonstrated signs of efficacy.
Additional Inclusion Criteria – Part B
1.Patients with metastatic recurrent disease histologically confirmed to be an adenocarcinoma subtype of NSCLC (adeno-NSCLC), or other tumor subtype(s) are eligible and must have exhausted all appropriate treatment options per local guidelines including progression on or after platinum-based chemotherapy; or must not have been a candidate for or must have received any
1. Chemotherapy treatments within 14 days prior to first dose of study treatment. For other anticancer treatments, treatment within 28 days or 5 half-lives, whichever shorter. If NSCLC with EGFRmt, osimertinib or other TKI treatments or cytotoxic chemotherapy within 14 days prior to first dose of study treatment. Prior toxicities must have resolved to grade 1 per CTCAE v 5.0 (except alopecia which must be no greater than Grade 2). For immunotherapy, including immune checkpoint inhibitors, within 28 days prior to the first dose of study treatment.
2. Experimental treatments within 4 weeks of first dose of BT5528 study treatment.
3. Current treatment with strong inhibitors or inducers of CYP3A4 or strong inhibitors of P-gp including herbal- or food-based.
4. Known sensitivity to any of the ingredients of investigational product or MMAE.
5. Significant medical condition, life-threatening illness, active uncontrolled infection or organ system dysfunction (such as ascites, coagulopathy, encephalopathy), or other reasons which could compromise patient’s safety, or interfere with or compromise study outcome integrity including consideration of gastrointestinal, skin and pulmonary co-morbidities and including review of screening chest CT to ensure no clinically significant co-morbidities.
6. Major surgery (excluding placement of vascular access) within 4 weeks of first dose of BT5528 study treatment and must have recovered adequately prior to starting study therapy
7. Receipt of live vaccine within 30 days of study treatment
8. Uncontrolled, symptomatic brain metastases (must have stable neurologic status following local therapy for at least 4 weeks without use of steroids or on stable or decreasing dose of less than or equal to 10 mg daily prednisone or equivalent and must be without neurologic dysfunction that would confound evaluation of neurologic and other AEs.)
9. Patients with uncontrolled hypertension (systolic BP =139 mmHg; diastolic BP =89 mmHg) prior to first dose of BT5528 study treatment (must have been in stable control for at least 3 months)
10. History or current evidence of any condition, therapy or laboratory abnormality that might confound study results , interfere with patient’s participation, or is not in the best interest of the patient to participate including but not limited to:
- Patients with history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, congestive heart failure or symptoms of NYHA Class III-IV documented within 6 months prior to first dose of BT5528 or:
i. Mean resting QTcF >470 msec
ii. Any factors that increase risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age, or any concomitant medication known to prolong the QT interval
iii. Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECGs, e.g., complete left bundle branch block, third degree heart block
11. Known HIV or AIDS
12. Patients with a positive hepatitis B surface antigen and/or anti-hepatitis B core antibody. Patients with a negative PCR assay are permitted with appropriate antiviral therapy
13. Active hepatitis C infection with positive viral load if hepatitis C virus antibody positive (if antibody is negative then viral load not applicable). Patients who have been treated for hepatitis C infect
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method