None listed
Conditions
Brief summary
This is a Phase 1/2, open label, multicenter study to evaluate the safety, tolerability, pharmacokinetics (PK) and clinical activity of escalating doses of BOS-342 monotherapy in patients with Hepatocellular Carcinoma (HCC) or other Glypican 3 (GPC3)-expressing tumors. Who is it for? You may be eligible for this study if you are aged 18 years or older, have histologically confirmed diagnosis of locally advanced, unresectable or metastatic HCC for which no standard curative therapy is available or other Glypican 3 (GPC3)-expressing tumors. Study details There are 2 Phases in this study. In Phase 1, all participants will be enrolled into small groups. Each group will receive a dose of BOS-342 administered intravenously (IV) every 2 weeks until radiologically documented progressive disease (PD), unacceptable toxicity, or occurrence of any criterion for withdrawal from the study or the study treatment. There will be up to six different dose levels tested to identify the highest tolerated dose of BOS-342. In Phase 2, participants will receive a dose level and schedule that is deemed safe and tolerable as determined in discussion among the Sponsor, Medical Monitor, and Safety Review Team (SRT) in Phase 1. Observations related to safety including TEAEs occurring within and beyond the DLT window, tolerability, compliance, PK, pharmacodynamic, ADA and preliminary efficacy will be included in the rationale supporting the selection of the Recommended Phase 2 dose (RP2D). Safety, tolerability, PK and clinical activity evaluations will be assessed in both phases. After completion of the Safety Follow-up visit, patients will be contacted every 3 months for survival status following the last dose of study drug. It is hoped that the information obtained from this study may help treat and improve the survival of future patients with HCC and other tumors
Interventions
BOS-342 (formerly known as PRS-342 and MPAL1073) is a monoclonal antibody (mAb)-like bispecific protein targeting the tumor antigen Glypican 3 (GPC3) and the costimulatory immunoreceptor 4-1BB (CD137). The anticipated mode of action of BOS-342 is to combine GPC3 binding in the tumor microenvironment with 4-1BB-induced T cell co-stimulation and expansion, leading to a higher local T cell activation and a reduced risk of systemic toxicity compared to monospecific 4-1BB targeting.
BOS-342 will be
BOS-342 (formerly known as PRS-342 and MPAL1073) is a monoclonal antibody (mAb)-like bispecific protein targeting the tumor antigen Glypican 3 (GPC3) and the costimulatory immunoreceptor 4-1BB (CD137). The anticipated mode of action of BOS-342 is to combine GPC3 binding in the tumor microenvironment with 4-1BB-induced T cell co-stimulation and expansion, leading to a higher local T cell activation and a reduced risk of systemic toxicity compared to monospecific 4-1BB targeting. BOS-342 will be administered intravenously (IV) every 2 weeks (Q2W) until radiologically documented progressive disease (PD), unacceptable toxicity, or occurrence of any criterion for withdrawal from the study or the study treatment. As per Protocol Amendment 3.0, all subjects who receive BOS-342 should receive antihistamines as well as prednisone (2 mg/kg, IV) or methylprednisolone (1.6 mg/kg, IV) as premedication prior to any BOS-342 infusion, commencing on C1D1. The recommended time of premedication of prednisone or methylprednisolone is 60-90 minutes prior to BOS-342 infusions. BOS-342 should be infused for 120 minutes. Additional dosing schedules may be explored based on available pharmacokinetics (PK), Pharmacodynamics (PD) and clinical activity. The study is comprised of 2 phases. Phase 1 is to assess the safety of BOS-342 and determine the maximum tolerated dose and/or recommended Phase 2 dose of BOS-342. Phase 2 is to evaluate the response rate in patients treated with BOS-342. - Phase 1 (dose escalation): Small groups of participants will be enrolled one at a time. The next group will receive a higher dose of BOS-342 bi-weekly if the previous group tolerated a lower dose. These groups will be enrolled until the highest tolerated dose of BOS-342 is identified. Additional participants may be enrolled in previously cleared dose levels while some participants may be treated at higher dose levels. - Phase 2 (dose expansion): Larger group of participants will be enrolled into the dose group selected from Phase 1. This group will receive a dose level and schedule that is deemed safe and tolerable as determined in Phase 1. Phase 2 is for collecting more information about the selected dose. A single treatment cycle is 28 days long, with BOS-342 administered intravenously (IV) on Day 1 and Day 15 of each cycle. The starting dose of BOS-342 (Dose Level 1) is 0.5 mg/kg intravenously (IV) every two weeks (Q2W). Dose escalation decisions will be based on the safety review of data collected in Cycle 1 (dose-limiting toxicity [DLT] period). Six Doses (intravenously, every two weeks) are planned to be assessed for Phase 1: (Dose Level 1) is 0.5 mg/kg, (Dose Level 2) is 1.5 mg/kg, (Dose Level 3) is 4.5 mg/kg, (Dose Level 4) is 9 mg/kg, (Dose Level 5) is 18 mg/kg and (Dose Level 6) is 27 mg/kg. Once the DLT period is met (28 days) for all patients enrolled to the evaluating-dose cohort, potential patients for the next cohort can begin screening. Once the safety data for the evaluating-dose cohort is evaluated by the Safety Review Team (SRT) and the decision is made to continue enrolling patients to the next dose cohort, patients can be treated at the dose determined by the SRT.
Sponsors
Boston Pharmaceuticals, Inc.
Study design
Allocation
Non-randomised trial
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Age 1. Patients must be greater than or equal to 18 years, at the time of signing the informed consent. Disease Characteristics 2. Histologically confirmed diagnosis of locally advanced, unresectable or metastatic HCC for which no standard curative therapy is available, or ineligible to accept/unable to tolerate standard therapy. 3. At least 1 unidimensional radiographically measurable lesion based on RECIST 1.1. 4. Availability of tumor biopsy: • Phase 1 only: availability of a fresh biopsy or archival tumor samples no older than 2 years prior to the first study drug administration. Tumor biopsies and tumor archival material must be suitable for biomarker assessment (at least 10 slides). Patients who do not have adequate archival tissue will require a biopsy during the screening period. Refer to the Laboratory Manual for further information. • Phase 2 only: availability of fresh tumor biopsy, or an archival tumor sample taken after the last anticancer treatment and prior to the first study drug administration. Tumor biopsies and tumor archival material must be suitable for biomarker assessment (at least 10 slides). Patients who do not have adequate archival tissue will require a biopsy during the screening period. Refer to the Laboratory Manual for further information. 5. GPC3 Expression: • Tumor samples are positive for GPC3 by local or central immunohistochemistry testing Organ Function and Performance Score within 10 days of treatment initiation 6. Karnofsky score greater than or equal to 50. 7. Adequate renal function as defined by an estimated creatinine clearance of greater than or equal to 60 mL/min/1.73 m2 according to the Cockcroft-Gault equation. 8. Adequate hepatic function defined as: • total bilirubin less than or equal to 1.5 × upper limit of normal (ULN) or normal conjugated bilirubin. • aspartate aminotransferase [AST] and alanine aminotransferase [ALT] less than or equal to 3 × ULN, or less than or equal to 5 × ULN if due to liver involvement by tumor. 9. Adequate bone marrow function defined as: • absolute neutrophil count greater than or equal to 1..5 × 109 cells/L. • hemoglobin greater than or equal to 9.0 g/dL. • platelets greater than or equal to 75 × 109 cells/L. 10. Adequate cardiac function defined as ejection fraction greater than 50% by echocardiogram, multigated acquisition (MUGA) or cardiovascular magnetic resonance imaging (MRI). Pregnancy and Contraception 11. All patients must be willing and able to comply with a highly effective contraceptive method (Appendix 4) during and for 3 months after the treatment period. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Informed Consent 12. Capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the ICF and in this protocol prior to initiation of any study procedures. 13. Willing and able to participate in the study and comply with all study requirements.
Exclusion criteria
Cancer and Previous Cancer Therapy 1. Any persistent clinically significant greater than or equal to Grade 2 toxicity from prior cancer therapy except alopecia or sensory neuropathy or immunotherapy-related thyroid toxicity requiring replacement therapy. 2. Active CNS metastasis. Exceptions: patients with stable brain metastases previously treated with surgery, radiotherapy or systemic therapy who are on a stable dose of steroids/anticonvulsants, with no dose change within 28 days prior to the first dose of study drug, are eligible to enroll. CNS lesions that have been radiated should not be selected as target lesions for the purposes of RECIST evaluation. 3. Cancer directed therapy (chemotherapy, radiotherapy, biologic, immunotherapy, hormonal therapy or other) within the shorter of 28 days or 5 half-lives, if known, of the first dose of study drug. Exception: palliative radiotherapy is allowed within 28 days prior to initiating treatment if associated toxicity resolved to less than or equal to Grade 1. However, lesions treated palliatively should not be selected as target lesions unless there has been clear progression of those lesions since the end of that treatment. 4. Prior or concurrent malignancy other than the malignancy under study, within the last 3 years. Exception: Patients with a history of a completely resected non-melanoma skin cancer or successfully treated in situ carcinoma or other malignancy for which there is very low risk of recurrence or progression are eligible. Prior/Concomitant Therapy 5. Major surgery within 28 days prior to the first dose of study drug. 6. Systemic corticosteroid therapy or any other form of systemic immunosuppressive medication within 1 week prior to the first dose of study drug. Exceptions: corticosteroid use as a premedication for IV contrast, transfusion therapy or prednisone less than or equal to 10 mg or equivalent per day for adrenal replacement or for patients with CNS disease, is permitted. 7. Live vaccine within 30 days prior to first day of treatment. Infections 8. Active hepatitis B, defined as hepatitis B virus (HBV) surface antigen positive and HBV core antibody positive with positive HBV deoxyribonucleic acid (DNA), or HBV positive core antibody alone with positive HBV DNA, unless meeting all of the following criteria: - Stable on antiviral therapy for hepatitis B virus (HBV) for at least 12 weeks. - Adherence to antiviral therapy during study therapy per local standard of care. - HBV viral load less than 200 IU / ml at screening 9. Active hepatitis C, defined as positive hepatitis C virus (HCV) antibody with positive HCV ribonucleic acid (RNA). 10. Known infection with human immunodeficiency virus (HIV), unless meeting all of the following criteria: • Stable on antiretroviral therapy (ART) for at least 4 weeks. • Adherence to ART during study therapy. • HIV viral load of less than 400 copies/mL at Screening (or undetectable per local criteria). • CD4 counts greater than or equal to 200/microliter. 11. Evidence or history of active or latent tuberculosis (TB) infection, defined as any 1 of the following: • Current clinical, radiographical, or laboratory evidence of active TB. • History of active TB. • Positive QuantiFERON-TB Gold In-Tube or other diagnostic test in the absence of clinical manifestations. 12. Active uncontrolled infection being treated with systemic antibiotic, antiviral, or antifungal therapy. Pregnancy and Breastfeeding 13. Pregnancy: Negative serum pregnancy test for females of child-bearing potential are required within 48 hours before the first dose of study intervention. 14. Breastfeeding or storage of breast milk. Organ Function 15. Uncontrolled or significant cardiovascular disease, including: • myocardial infarction, unstable angina or stroke/transient ischemic attack within the past 6 months. • history of clinically significant arrythmias (such as atrial fibrillation, ventricular tachycardia, ventricular fibrillation or torsade de pointes). • history of other clinically significant heart disease (e.g., New York Heart Association (NYHA) Class II or greater congestive heart failure, pericarditis, cardiac amyloidosis, significant pericardial effusion). 16. Liver cirrhosis classified as Child-Pugh Class B (greater than 7) or C. Concurrent Conditions 17. Uncontrolled or severe concurrent medical condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate. Any patient who experiences a Grade 3 or higher AE during the screening period needs to be discussed with the Medical Monitor and Sponsor to confirm eligibility. 18. Uncontrolled intercurrent illness or psychiatric illness/social situation that would limit compliance with study requirements. 19. Clinically significant autoimmune disease, or history of greater than or equal to Grade 3 immune-mediated adverse event due to a checkpoint inhibitor or similar therapy. 20. Solid organ transplant. Other Exclusions 21. Patient not available to complete all protocol required study visits or procedures to the best of the patient’s ability and Investigator’s knowledge. 22. History or evidence of any other clinically significant condition or disease (with the exception of those outlined above) that, in the opinion of the Investigator, would be a risk to patient safety or interfere with the study evaluation, procedures, or completion.
Outcome results
None listed