MC# 21-17 - A Phase I/II Dose Escalation and Dose Expansion Study of BA3021 Alone and in Combination with Nivolumab in Patients with Advanced Solid Tumors
Disease Type(s): Melanoma, Lung-NSCLC
Drug Classification(s): Targeted Therapy, Antibody Drug Conjugate
Molecular Target(s): ROR2
Mechanism of Action
BA3021, the anti-ROR2 antibody, is designed to have pH-sensitive binding to restrict its activity to the typically acidic tumor microenvironment. The antibody target is ROR2, a transmembrane receptor for WNT, that may be overexpressed in tumors.
In this study, the sponsor and investigators want to learn:
- About the safety and tolerability of BA3021 alone or in combination with Nivolumab
- How proteins that indicate the status of your disease are affected with use of BA3021
- If BA3021 alone or in combination with Nivolumab prevents or delays tumor growth or shrinks existing tumors
- How quickly BA3021 is removed from your the blood
- Phase 1: Histologically or cytologically confirmed locally advanced unresectable or metastatic solid tumor and have failed all available SoC therapy and for whom no curative therapy is available or who are not eligible, intolerant to or refuse standard therapy.
- Phase 2: Patients must:
- Have histologically or cytologically confirmed locally advanced unresectable or metastatic NSCLC or melanoma.
- Have prior disease progression on or after receiving a PD-1/L-1 (NSCLC and melanoma patients), EGFR inhibitor (NSCLC), or ALK inhibitor (NSCLC).
- Documented progression according to RECIST v1.1 criteria within the 6 months prior to enrollment.
- At least one measurable lesion according to RECIST v1.1. Previously radiated tumor lesion should not be considered a target lesion.
- Age ≥ 18 years.
- ECOG performance status of 0 or 1.
- Life expectancy of at least 3 months.
- In Phase 1 dose expansion and Phase 2, must have ROR2-positive disease determined by BioAtla ROR2 immunohistochemistry (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. For Phase 1 dose expansion, the ROR2 expression cutoff is ≥ 1+ in ≥ 10% tumor cells. For Phase 2 Part 1, a TmPS ≥ 1% (consisting of 1+, 2+, and 3+ intensities) is considered positive. For Phase 2 Part 2, the ROR2 TmPS cut-off will be determined based on data from Phase 1 and Phase 2 Part 1.
- Tissue amenable to biopsy or archived tumor tissue must be available to the Sponsor for ROR2 and other gene expression testing. Fresh biopsy is preferred*. 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 of the sample 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. *Note: Tumor tissue samples taken after having disease progression on a PD-1/L1, EGFR, or ALK inhibitor are much more likely to express higher levels of target antigen that may enable a candidate to participate in the study.
- Must have:
- Completed (and recovered from treatment-related toxicities) any prior treatment with radiotherapy, chemotherapy, or targeted small molecule therapy and/or treatment with other investigational anticancer agents at least 5 half-lives or 2 weeks prior to first study dose, or biologics (such as a monoclonal antibody [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:
- ANC ≥ 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 ≤ 5 × ULN if metastasis in liver.
- Phase 2 only: Albumin > 3.0 g/dL
- 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 BA3021, 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 BA3021 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 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 while included in the study and for 6 months after the last infusion of BA3021.
- Provide written informed consent (patient or their legally acceptable representative).
- 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 BA3021 dose may not be greater than 1.2 mg/kg Q3W (Day 1) or 1.2 mg/kg 2Q3W (Days 1 and 8).
- Severe renal impairment (creatinine clearance [CrCL] < 30 mL/min).
- Known non-controlled CNS metastasis.
- Phase 1 only: Received granulocyte colony stimulating factor (G-CSF) or granulocyte/macrophage colony stimulating factor support 3 weeks prior to first BA3021 administration.
- A history of ≥ Grade 3 allergic reactions to monoclonal antibody therapy as well as known or suspected allergy or intolerance to any agent given during this study.
- Major surgery within 4 weeks before first BA3021 administration.
- Known intracerebral arteriovenous malformation, cerebral aneurysm, or stroke. Patients treated and 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 (in the judgment of the Investigator) active viral, bacterial or fungal infection requiring systemic antibiotics/antivirals/antifungals.
- Known history of testing positive for human immunodeficiency virus (HIV) infection or known acquired immunodeficiency (AIDS).
- Known active hepatitis B (e.g., HBsAg reactive) or active 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.
- Phase 1 only: Using concurrent therapy with corticosteroids at greater than or equal to 12 mg/day prednisone equivalent.
- 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.
- For Phase 2 only, to be eligible for the combination arm with nivolumab in Part 1 and Part 2 of the study:
- 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 entry to study entry.
- Active, known, or suspected autoimmune disease are excluded. 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 that required 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.
- Intolerance to prior PD-1 treatment. Prior PD-1 treatment must not have been discontinued for severe or recurrent severe toxicity (including myocarditis, or other myocardiotoxicity, encephalitis, colitis, diarrhea, pancreatitis, hypo/hyperthyroidism, hypopituitarism, adrenal insufficiency, rash, autonomic neuropathy, myasthenia gravis, Guillain-Barre, myositis/polymyositis, hepatitis, nephritis, Type 1 diabetes, thrombocytopenia).
- Dallas, TX - Mary Crowley Cancer Research - Medical City