A Camelid Nanobody B7-H3 Tri-Specific Killer Engager (GTB-5550) for the Treatment of Advanced Solid Tumors that Failed Prior Therapy

Inclusion Criteria

• Diagnosis of one of the eligible tumor types with histologically- or cytologically-confirmed advanced/metastatic disease. Intolerant of treatment includes the following: prior treatment-related toxicity that was clinically significant, persistent, or recurrent despite optimal management, a documented serious hypersensitivity or allergic reaction, contraindications based on comorbid conditions, organ dysfunction, or other medically justified reasons based on investigators clinical judgement * Castration-resistant prostate cancer (CRPC): ** Failure of at least 1 line of prior therapy in the castrate- resistant setting. Prior treatment with taxanes and radioligand therapies are allowed, but not required ** Subjects must have received at least one prior systemic regimen and have no other therapy available known to provide meaningful clinical benefit in the opinion of the investigator, or subject refuses, is intolerant to, or is considered ineligible for standard therapies or other available therapy options * Recurrent epithelial ovarian cancer (OC) including fallopian tube, and primary peritoneal cancer: ** Recurrent platinum-resistant epithelial ovarian cancer. Platinum-resistance is defined as disease that has responded to initial chemotherapy but demonstrates recurrence within ≤ 6 months following completion of platinum-based therapy. Patients must have received bevacizumab (first-line or in recurrent setting) if clinically indicated and mirvetuximab soravtansine if folate receptor alpha-positive, unless the patient is documented as intolerant or refractory. Subjects must have no other therapy available known to provide meaningful clinical benefit in the opinion of the investigator, or subject refuses, is intolerant to, or is considered ineligible for standard therapies or other available therapy options ** Recurrent platinum-sensitive epithelial ovarian cancer. Platinum-sensitivity is defined as disease that has recurred >= 6 months after completion of platinum-based chemotherapy. Patient has to have received at least 2 prior regimens in the recurrent setting to be eligible for this study. Subjects must have no other therapy available known to provide meaningful clinical benefit in the opinion of the investigator, or subject refuses, is intolerant to, or is considered ineligible for standard therapies or other available therapy options * Metastatic breast cancer: ** Failure of at least 2 lines of prior systemic therapy in the metastatic setting, including estrogen receptor (ER)/progesterone receptor (PR) or HER2-targeting agents specific for that patient's histology, without other approved therapeutic options. Subjects must have no other therapy available known to provide meaningful clinical benefit in the opinion of the investigator, or subject refuses, is intolerant to, or is considered ineligible for standard therapies or other available therapy options * Non-small cell lung cancer (NSCLC): ** Failure or progression of standard of care therapy including prior chemotherapy and prior anti-PD-(L)1 antibody (separately or in combination) and are not amenable to surgical resection or other approved therapeutic options that have demonstrated clinical benefit. NSCLC subjects with actionable gene alterations e.g., EGFR mutations or ALK/ROS1 gene rearrangements are eligible if they have failed all approved targeted therapeutic options. Subjects must have no other therapy available known to provide meaningful clinical benefit in the opinion of the investigator, or subject refuses, is intolerant to, or is considered ineligible for standard therapies or other available therapy options * Squamous cell carcinoma of the head/neck (SCCHN), including those with molecularly-confirmed franconi anemia (FA): ** Failure of or progression following treatment with a platinum-based regimen (administered in any line of therapy) and PD-1/PD-L1 antagonist administered in the recurrent or metastatic setting. Definitive chemoradiation with carboplatin/cisplatin counts as a prior line of therapy. Subjects must have no other therapy available known to provide meaningful clinical benefit in the opinion of the investigator, or subject refuses, is intolerant to, or is considered ineligible for standard therapies or other available therapy options. ** Patients with a molecularly-confirmed diagnosis of FA are permitted to enroll on the trial if they have unresectable locally advanced or metastatic SCCHN which is ineligible for or has failed radiation therapy * Metastatic pancreatic cancer: ** Failure of at least 2 lines of prior systemic therapy, including fluorouracil, irinotecan, leucovorin calcium, and oxaliplatin (FOLFIRINOX) or derivative in the first line. Subjects with actionable gene alterations e.g., BRCA1/2 mutations and other molecularly-directed agents are eligible if they have failed all approved targeted therapeutic options. Subjects must have no other therapy available known to provide meaningful clinical benefit in the opinion of the investigator, or subject refuses, is intolerant to, or is considered ineligible for standard therapies or other available therapy options * Bladder (urothelial) cancer: ** Failure of at least 2 lines of prior systemic therapy, including enfortumab vedotin +/- pembrolizumab and platinum-based chemotherapy (if eligible), HER2-targeted therapy (if eligible), and FGFR-targeted therapy (if eligible). Subjects must have no other therapy available known to provide meaningful clinical benefit in the opinion of the investigator, or subject refuses, is intolerant to, or is considered ineligible for standard therapies or other available therapy options
• Measurable disease by RECIST 1.1 (Eisenhauer 2009) * An exception is permitted for metastatic CRPC (mCRPC) with bone metastases only - assessed per Prostate Cancer Clinical Trials Working Group 3 (PCWG3) (Scher 2015)
• Meet the disease-specific criteria for prior failed therapy (refer to above table)
• Must be refractory to, intolerant of (basis of intolerance must be documented in the medical record and study case report form), or not eligible for existing therapy(ies) known to provide clinical benefit for their condition
• Age ≥ 18 years of age at time of consent
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
• Hemoglobin ≥ 9 g/dL (within 14 days [30 days for cardiac] of cycle 1 day 1) (may be transfused not more than 2 units of pRBCs within 7 days prior to cycle 1 day 1 to meet this requirement)
• Absolute neutrophil count (ANC) ≥ 1500/ul (within 14 days [30 days for cardiac] of cycle 1 day 1) * Granulocyte colony-stimulating factor (G-CSF) is not allowed to achieve ANC threshold or within 7 days of cycle 1 day 1
• Platelets ≥ 100 x 10^9/L (within 14 days [30 days for cardiac] of cycle 1 day 1) (may be transfused not more than 2 unit of platelets within 7 days prior to cycle 1 day 1 to meet this requirement)
• Absolute lymphocyte count (ALC) ≥ 300/ul (within 14 days [30 days for cardiac] of cycle 1 day 1)
• Albumin ≥ 3.0 g/dL (within 14 days [30 days for cardiac] of cycle 1 day 1)
• A patient body surface area (BSA) corrected glomerular filtration rate ≥ 45 mL/min as calculated using the Modified Cockroft-Gault equation (Rostoker et al. 2007) (within 14 days [30 days for cardiac] of cycle 1 day 1)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 1.5 x upper limit of normal (ULN) (within 14 days [30 days for cardiac] of cycle 1 day 1)
• Total bilirubin ≤ 1.5 x ULN (within 14 days [30 days for cardiac] of cycle 1 day 1)
• New York Heart Association (NYHA) class I or II (within 14 days [30 days for cardiac] of cycle 1 day 1)
• Left ventricular ejection fraction (LVEF) ≥ 45% by echocardiogram or cardiac MRI (within 14 days [30 days for cardiac] of cycle 1 day 1)
• Adequate pulmonary function with pulmonary function tests (PFTs) > 50% forced expiratory volume in 1 second (FEV1) if symptomatic or known impairment
• Sexually active persons of childbearing potential or persons with partners of childbearing potential must agree to use a highly effective form of contraception during study treatment and for at least 4 months after the last dose of GTB-5550. Non-childbearing is defined as > 1 year post-menopausal or surgically sterilized. * Examples of highly effective birth control methods include but are not limited to the following: ** Double-barrier contraception by using a condom AND spermicidal jelly or foam, or a diaphragm AND spermicidal jelly or foam ** Oral contraceptive pills ** Injectable contraception (i.e., Depo Provera) ** Intrauterine device (IUD) ** Transdermal contraceptive patch ** Vaginal contraceptive ring ** Contraceptive implants ** Abstinence * Note: Rhythm method alone is not considered an adequate method of contraception
• Must have a caregiver through the cycle 1 day 14 visit for the Phase 1a portion of the study only
• Must agree to stay within a 60-minute drive of the study center through the cycle 1 day 15 visit for the Phase 1a portion of the study only
• Provides voluntary written consent prior to the performance of any research related activity

Exclusion Criteria

• Pregnant or breast-feeding or planning pregnancy within 4 months after the last dose of GTB-5550. The effect of GTB-5550 on the fetus is unknown. Persons of childbearing potential must have a negative serum or urine test within 7 days prior to cycle 1 day 1 to rule out pregnancy
• Anti-cancer treatment including surgery, radiotherapy, chemotherapy, other immunotherapy, or investigational therapy within 14 days prior to the 1st dose of GTB-5550. Radioligand therapy requires at least 1 cycle washout (6 weeks for Pluvicto, 4 weeks for Xofigo)
• Prior malignancy other than the one under treatment except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer currently in complete remission, or any other cancer from which the patient has been disease-free for 1 year after surgical treatment or other definitive treatment
• Prior organ allograft or allogeneic transplantation. An exception is made for FA patients with prior history of allogeneic hematopoietic stem cell transplant off immune suppressive therapy for > 1 year
• New or progressive pulmonary infiltrates on screening chest x-ray or chest computed tomography (CT) scan unless cleared for study by pulmonology. Infiltrates attributed to infection must be stable/improving with associated clinical improvement after 1 week of appropriate therapy (4 weeks for presumed or documented fungal infections)
• Active systemic infection requiring parenteral antibiotic therapy. Any prior systemic infections must have resolved to grade 1 or lower following optimal therapy
• Active HIV with virus detectable by polymerase chain reaction (PCR) and stably on highly-active antiretrovial treatment (HAART) * Participants with a history of HIV and undetectable viral load while on stable highly active antiretroviral therapy (HAART) are permitted. These participants must be willing to undergo monthly polymerase chain reaction (PCR) HIV ribonucleic acid (RNA) testing
• Active hepatitis B or hepatitis C (virus detectable by PCR) - chronic asymptomatic viral hepatitis is allowed * Participants with occult or prior hepatitis B infection (defined as positive hepatitis B virus core antibody [HBcAb] and negative hepatitis B virus surface antigen [HBsAg]) may be included if hepatitis B virus (HBV) deoxyribonucleic acid (DNA) is undetectable. These participants must be willing to undergo monthly polymerase chain reaction (PCR) HBV DNA testing
• Positive test results from chronic hepatitis B infection (defined as positive HBsAg serology) and/or positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology test). * Participants who are positive for HCV antibody are eligible only if PCR is negative for HCV RNA
• Active or untreated central nervous system (CNS) metastases or symptoms of CNS spread within 14 days prior to day 1. * Persons previously treated for CNS metastases may be eligible provided they have completed radiotherapy at least 14 days prior to enrollment, are asymptomatic, and require ≤ 10 mg daily prednisone equivalent
• Active autoimmune disease that has required systemic treatment (except replacement therapy) within the past 1 year or any other diseases requiring immunosuppressive therapy while on study. Inhaled or topical steroids, and adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
• The potential risk of QT/corrected QT interval (QTc) prolongation is unknown in humans receiving GTB-5550; therefore, either of the following is an exclusion criteria: * QTc interval > 480 msec at screening * A family history of long QT syndrome
• Psychiatric illness/social situations that, in the judgement of the enrolling investigator, would limit compliance with study requirements
• Other illness or a medical issue that, in the judgement of the enrolling investigator, would exclude the patient from participating in this study