Phase Ib Study of CBP-1019 in Combination with FOLFOX +/- Bevacizumab, Pembrolizumab, or Enzalutamide for Metastatic TRPV6-overexpressing Solid Tumors of Epithelial Origin

Eligibility Criteria

• 1. Patients must have histologically or cytologically confirmed malignancy of epithelial origin other than ovarian cancer that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective. Patients must have received at least one prior line of systemic standard therapy, and have either disease progression or intolerable toxicity after standard treatment.
• 2. In the dose expansion, Regimen A will enroll patients with metastatic pancreatic cancer, Regimen B will enroll patients with metastatic colorectal cancer, Regimen C will enroll patients with metastatic solid tumors of epithelial origin who have received prior anti-PD-(L)1 therapy, and Regimen D will enroll patients with metastatic castration-resistant prostate cancer.
• 3. Hormonal therapy specific for prostate cancer is allowed to continue at the discretion of the treating physician.
• 4. Patients (with the exception of those with prostate cancer) must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) ≥10 mm (≥1 cm) with computed tomography (CT) scan, magnetic resonance imaging (MRI) scan, or calipers by clinical exam.
• 5. Ability to understand and the willingness to sign a written informed consent document.
• 6. Age ≥18 years.
• 7. Eastern Cooperative Oncology Group (ECOG) performance status of ≤1 (Appendix 1).
• 8. Must have adequate organ and marrow functions as defined below:
• * Urinalysis ≤1 proteinuria, or urine protein/creatinine ratio (UPCR) ≤1 mg/mg (≤113.2 mg/mmol), or 24-h urine protein ≤1 g (applies to bevacizumab-based regimen only).
• * Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) ≤1.5× ULN if not on therapeutic anticoagulation.
• * Serum creatinine ≤1.5× ULN or calculated creatinine clearance (CrCl) ≥50 mL/min by the Cockcroft-Gault method as below or 24-hour urine collection. CrCl = (140-age) × (weight/kg) x Fa / (72 × serum creatinine mg/dL). a where F= 0.85 for females and F=1 for males
• 9. Patients whose baseline pulse oximetry is at least 90% on room air.
• 10. Fridericia's corrected QT interval (QTcF =QT/60) ≤460 ms for males and ≤480 ms for females on electrocardiogram (ECG) conducted at rest during screening.
• 11. The effects of study drugs on the developing human fetus are unknown. For this reason and because Class II drugs as well as other therapeutic agents used in this trial are known to be teratogenic, women of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry, throughout the study treatment period, and for 6 months after study treatment completion (Refer to Pregnancy Assessment Policy MDACC Institutional Policy # CLN1114). This includes all female patients, between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following:
• 12. Females of childbearing potential must have a negative serum pregnancy test within 3 days prior to study treatment initiation (Cycle 1 Day 1).
• 13. Men and women enrolled on this protocol must agree to use adequate contraception during the study treatment period and for 6 months after completion of study treatment.
• 14. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimens are eligible for this trial.
• 15. Agree to provide baseline tumor specimens: archival tissue block, or 10 FFPE slides, or a pretreatment biopsy.
• 1. Patients must have adequate washout from prior therapy at the time of study treatment initiation: 3 weeks from any treatment specifically for systemic tumor control; 2 weeks from cytotoxic agents that were administered weekly; 6 weeks from nitrosoureas or mitomycin C; and 5 half-lives from targeted agents with half-lives and pharmacodynamic effects lasting \<5 days.
• 2. Has received an investigational non-myelosuppressive agent within 14 days prior to study treatment initiation or an investigational myelosuppressive agent within 21 days prior to study treatment initiation.
• 3. Uncontrolled intercurrent illness including but not limited to:
• * History of myocardial infarction, unstable angina, stroke, or transient ischemic attack within 6 months before study enrollment.
• * Lesions invading or encasing any major blood vessels and cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation; uncontrolled hypertension defined as sustained blood pressure \>140 mmHg systolic / \>90 mmHg diastolic despite optimal antihypertensive treatment (applies to bevacizumab-based regimen only).
• * History or current evidence of uncontrolled ventricular arrhythmia.
• * Congenital long QT syndrome, or any known history of torsade de pointes, or family history of unexplained sudden death.
• * Clinically significant bleeding or active gastric or duodenal ulcer.
• * Chronic diarrhea disease considered to be clinically significant by the investigator.
• * Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before the first dose of study treatment, or any GI disorders associated with a high risk of perforation or fistula formation.
• * Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study.
• 4. Unresolved clinically significant Grade ≥1 toxicity from prior therapy.
• 5. History of allergic reactions to the study drugs or any of their components.
• 6. Has not recovered from a major surgical procedure or significant traumatic injury (i.e., still needing additional surgical or medical care for these issues): major surgical procedures ≤28 days prior to study entry or minor surgical procedures ≤7 days prior to study entry. No waiting period is required following port-a-cath or other central venous access placement. Patients must have complete wound healing from major or minor surgery before the first dose of study treatment.
• 7. Currently receiving an investigational drug in a clinical trial or participating in any other type of medical research judged not to be scientifically or medically compatible with this study. If a patient is currently enrolled in a clinical trial involving non-approved use of a therapeutic device for cancer control, then agreement with the investigator and the Sponsor is required to establish eligibility.
• 9. Symptomatic primary tumors or metastasis in the brain and/or central nervous system (CNS) that are uncontrolled with antiepileptics and/or require prednisone \>10 mg/day or equivalent.
• 10. Evidence of leptomeningeal or lymphangitic carcinomatosis.
• 11. Breastfeeding or pregnant.
• 12. Known history of positive test for human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV).
• * Have a T cell (CD4+) count ≥350 cells/L.
• * No history of opportunistic infections or other malignancies.
• * Have an HIV viral load less than 400 copies/mL.
• * In the opinion of the investigator, their antiretroviral therapy or other HIV treatments will not interfere with the activity of the investigational product or cause any confusion with the assessment of the investigational drug toxicities.
• * Negative viral load test (HBV DNA or HCV RNA) at screening.
• 13. Ability to take oral medications without medical history of malabsorption or other chronic GI disease, or other conditions that may hamper compliance and/or absorption of the study agent (applies to enzalutamide-based regimen only).
• 14. Concurrent immunosuppressive therapy or steroid therapy (\>10 mg/day prednisone or equivalent) (applies to pembrolizumab-based regimen only).
• 15. History of autoimmune disease including but not limited to inflammatory bowel disease, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoidarthritis, inflammatory bowel disease, Wegener's granulomatosis, Sjögren's syndrome, GuillainBarré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis that required systemic therapy in the past 2 years (applies to pembrolizumab-based regimen only).
• 16. History of Grade ≥3 immune-related AEs from previous immunotherapy (applies to pembrolizumab-based regimen only).
• 17. History of interstitial lung disease or (non-infectious) pneumonitis that required steroids or current pneumonitis (applies to pembrolizumab-based regimen only).
• 18. History of Grade ≥3 allergic reaction to treatment with a monoclonal antibody (applies to bevacizumab-based and pembrolizumab-based regimens only).