MC# 21-28 - A Phase I/II Dose Escalation and Dose Expansion Study of BA3011 Alone and in Combination with Nivolumab in Adult and Adolescent Patients 12 Years and Older with Advanced Solid Tumors
Disease Type(s): Sarcoma
Drug Classification(s): Antibody Drug Conjugate
Molecular Target(s): AXL
Mechanism of Action
BA3011, an anti-AXL antibody, is designed to have pH-sensitive binding to restrict its activity to the typically acidic tumor microenvironment. The Antibody target is AXL, a transmembrane that may be overexpressed in Non-Small Cell Lung Cancer and other malignancies.
In this study, the sponsor and investigators want to learn:
- About the safety and tolerability of BA3011 alone or in combination with Nivolumab
- How proteins that indicate the status of your disease are affected with use of BA3011
- How much of BA3011 is absorbed into the blood and how fast it is removed
- If your body develops proteins that work against BA3011
- If research tests can be used in the future to predict who will benefit from BA3011
- If BA3011 alone or in combination with Nivolumab prevents or delays tumor growth
- Phase 2: Patients must:
- Have histologically or cytologically confirmed locally advanced unresectable or metastatic sarcoma
- Have documented progression according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria within the 6 months prior to enrollment. The requirement for documented progression does not apply to sarcoma subtypes for which no treatment is approved.
- Be ineligible for chemotherapy or have received at least 1 regimen containing anthracycline and a maximum of 3 previous lines of approved systemic therapy for metastatic disease (no more than 2 lines of combination regimens), including pazopanib, trabectedin, eribulin mesylate, or tazemetostat, if applicable per regional prescribing information. The requirements for prior treatments do not apply to sarcoma subtypes for which no treatment is approved.
- Measurable disease according to RECIST v1.1. Previously radiated tumor lesion should not be considered a target lesion.
- Phase 2: Age ≥ 12 years
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- For Pediatric patients between the age of 16 years old and 17 years old (inclusive), the Karnofsky scale can be used. The grade must be ≥ 70 for the patients to be eligible for the study.
- For Pediatric patients between the age of 12 years old and 15 years old (inclusive), the Lansky scale can be used. The grade must be ≥ 70 for the patients to be eligible for the study.
- Life expectancy of at least 3 months
- Archived tumor tissue or tissue amenable to biopsy must be available to the Sponsor for AXL and other gene expression testing. All patients must consent to provide a pretreatment tumor specimen for biomarker studies. For older archival samples (e.g., obtained more than 12 months before Screening), Sponsor approval must be obtained. If archival tissue is unavailable, patients must consent to undergo a tumor biopsy during screening. Core needle (a minimum of 3 core samples are required) or excisional biopsies or resected tissue specimens are required.
- In Phase 1 dose expansion and Phase 2, patients must have AXL-positive disease determined by BioAtla AXL IHC assay based on archival tissue or biopsy; a minimum of 3 core samples are required to ensure a sufficient quantity of cells are obtained. Core needle or excisional biopsies, or resected tissue is required. For Phase 1 dose expansion, the AXL expression cutoff is ≥ 1+ in ≥ 10% tumor cells. For Phase 2, a percent score ≥ 50 (consisting of 1+, 2+, and 3+ intensities) is considered positive.
- Must have:
- Completed (and recovered from treatment-related toxicities) any prior treatment with radiotherapy, chemotherapy, and/or treatment with other investigational anticancer agents at least 5 half-lives or 2 weeks, prior to first study dose. Biologics (such as a mAb) at least 4 weeks prior to first study dose. Exceptions are bisphosphonates, denosumab, and gonadotropin-releasing hormone agonist or antagonist.
- Completed any prior treatment with nitrogen mustard agents, melphalan, or carmustine (BCNU) therapy at least 6 weeks prior to first study dose
- Received any prior autologous hematopoietic stem cell infusion at least 8 weeks prior to first study dose
- Adequate organ functions. The following are required baseline laboratory values:
- Absolute neutrophil count ≥ 1,500/μL or 1.5 × 109/L
- Platelets ≥ 100,000/µL or 100 × 109/L
- Hemoglobin ≥ 9.0 g/dL
- Bilirubin ≤ 1.5 × upper limit of normal (ULN)
- Serum creatinine ≤ 1.5 × ULN
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN; ALT and AST ≤ 3 × ULN if metastasis in liver
- INR < 1.7 or prothrombin time < 4 seconds above control (Phase 2 only)
- Albumin > 3.0 g/dL (Phase 2 only)
- Available for periodic blood sampling, study-related assessments, and management of toxicity at the treating institution and be willing to comply with the expected drug administration schedule
- Prior to the first dose of BA3011, female patients of childbearing potential must have a negative serum or urine pregnancy test result, and throughout the study and for 6 months after the last dose of BA3011 must agree to use an effective contraceptive method (either a barrier/intrauterine method or a hormonal method)
- Female patients of childbearing potential, regardless of their age, are those who are considered fertile following menarche and until becoming post-menopausal unless permanently sterile
- Female patients of non-child-bearing potential are those who are premenarchal, who are postmenopausal greater than 1 year, or who have had a bilateral tubal ligation or hysterectomy
- Male patients of reproductive potential must agree to use effective contraception throughout the study and for 6 months after the last dose of BA3011
- Provide written informed consent (patient or their legally acceptable representative or legal guardian[s]). Patient assent must be obtained for patients < 18 years old.
- Clinically significant cardiac disease, in the judgment of the Investigator
- Known congestive heart failure (New York Heart Association classes II-IV) or serious cardiac arrhythmia requiring treatment; patients with stable condition and medication for ≥3 months can be enrolled
- Moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. For Phase 1 only, patients with mild (Child-Pugh A) hepatic impairment, the initial BA3011 dose may not be greater than 1.2 mg/kg 1Q3W (Day 1) or 1.2 mg/kg 2Q3W (Days 1 and 8).
- Severe renal impairment (CrCL less than 30 mL/min)
- Known non-controlled central nervous system (CNS) metastasis
- A history of ≥ Grade 3 allergic reactions to mAb therapy as well as known or suspected allergy or intolerance to any agent given during this study
- Major surgery within 4 weeks before first BA3011 administration
- Known intracerebral arteriovenous malformation, cerebral aneurysm, or stroke. Patients treated with stable condition for ≥ 3 months can be enrolled.
- Prior therapy with a conjugated or unconjugated auristatin derivative/vinca-binding site targeting payload
- Known additional malignancy that is active and/or progressive requiring treatment; patients with other malignancies that have been definitively treated and who have been rendered disease free will be eligible
- Ongoing peripheral sensory or motor neuropathy > Grade 1 or recent (6 months) onset of Grade 1 neuropathy and/or prior history of any > Grade 2 neuropathy of any etiology and/or any hereditary neuropathy, including, but not limited to Charcot-Marie-Tooth disease
- Clinically significant active viral, bacterial or fungal infection requiring systemic antibiotics/antivirals/antifungals
- Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
- Known active hepatitis B (e.g., HBsAg reactive) or hepatitis C (e.g., HCV RNA [qualitative] is detected)
- Women who are pregnant or breast feeding
- Using concurrent therapy with other anti-neoplastic or experimental agents
- Using moderate or strong CYP3A4 inducers or inhibitors, including cannabidiol
- Using P-glycoprotein (P-gp) inhibitors
- Any serious underlying medical condition that, in the opinion of the Investigator or Medical Monitor, would impair their ability to receive or tolerate the planned treatment. In such cases, the Sponsor-designated Medical Monitor must review each case prior to patient enrollment.
- Any clinically significant pleural, pericardial, and/or peritoneal effusion (e.g., effusion affecting normal organ function and/or requiring percutaneous drainage or diuretic control)
- Any history of hepatic encephalopathy; any current clinically significant ascites, as measured by physical examination; or active drug or alcohol abuse
- To be eligible for the combination arm with nivolumab (Phase 2 only):
- A history of interstitial lung disease, non-infectious pneumonitis, or uncontrolled diseases, including pulmonary fibrosis, acute lung diseases, etc.
- Administered a live vaccine ≤ 4 weeks before enrollment. Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed. Inactivated SARS-CoV-2 vaccines are allowed and recommended prior to study entry.
- Active, known, or suspected autoimmune disease. Patients with type 1 diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger may be permitted to enroll.
- Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before enrollment. Note: Patients who are currently or have previously been on any of the following steroid regimens are not excluded:
- Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent)
- Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal systemic absorption
- Short course (≤ 7 days) of corticosteroid prescribed prophylactically (e.g., for contrast dye allergy) or for the treatment of a non-autoimmune condition (e.g., delayed-type hypersensitivity reaction caused by contact allergen)
- Prior allogeneic stem cell transplantation or organ transplantation
- Dallas, TX - Mary Crowley Cancer Research - Medical City