A Phase 1 in Patients With HLA-A*0201+ and WT1+ Recurrent/Metastatic Cancers

CUE-102 is a novel fusion protein developed for the treatment of patients with WT1-positive malignancies by selective engagement and expansion of tumor antigen-specific T cells that should allow for increased potential for anti-cancer efficacy and reduced toxicity relative to non-targeted forms of immunotherapy that result in systemic activation of the immune system.

The goal of Part A is to characterize the safety, tolerability, and biological effects of CUE-102.

The goal of Part B is to expand the safety and immune activity data at the RP2D identified in Part A, and to evaluate antitumor activity at this dose.

Inclusion criteria

• Ability to provide informed consent and documentation of informed consent prior to initiation of any study-related tests or procedures that are not part of standard of care for the patient's disease.
• Age ≥18 years old
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Life expectancy ≥12 weeks
• Measurable disease as per RECIST 1.1 and documented by CT and/or MRI.
• All tumors must have histologically or cytologically confirmed cancer diagnosis
• Patients must have any of the following cancers to be eligible:

A. Colorectal cancer

• Histologically or cytologically documented adenocarcinoma of colon or rectum at the time of initial presentation
• Metastatic or locally advanced/unresectable disease
• Documented disease progression after the last administration of standard therapies or intolerance to at least 2 prior systemic treatment regimens (CUE-102 will be 3rd line therapy or greater).

B. Gastric cancer (including gastroesophageal junction)

• Histologically or cytologically documented gastric cancer at the time of initial presentation
• Metastatic or locally advanced/unresectable disease
• Documented disease progression after last administration of standard therapies or intolerance to standard therapies. (CUE-102 will be 2nd line therapy or greater).

C. Pancreatic cancer

• Histologically or cytologically documented pancreatic adenocarcinoma at the time of initial presentation
• Patients with metastatic or locally advanced/unresectable disease.
• Prior systemic treatment must include either a fluoropyrimidine-based or gemcitabine-based regimen in either the (neo)adjuvant or relapsed setting. (CUE-102 will be 2nd line therapy or greater).

D. Ovarian cancer

• Histologically or cytologically documented ovarian cancer at the time of initial presentation
• Metastatic or locally advanced/unresectable disease, with documented disease progression after last administration of standard therapies or intolerance to standard therapies.
• Prior systemic treatment must include a platinum-based regimen. (CUE-102 will be 2nd line therapy or greater).
• For patients determined to have platinum-sensitive disease, treatment with a second platinum-based combination regimen +/- bevacizumab should be considered prior to treatment with CUE-102 (CUE-102 will be 3rd line therapy or greater).
• Patient must have HLA-A*0201 genotype as determined by genomic testing.
• Patient must have histologically and/or cytologically proven tumor(s) that is WT1 positive.
• Acceptable laboratory parameters.
• Female patients of childbearing potential must agree to use acceptable contraceptive measures from the time of main study consent through 90 days after discontinuation of study drug administration.
• Non-vasectomized male patients with partners of childbearing potential must use barrier contraception from the time of main study consent through 90 days after discontinuation of study drug.
• Patients who have previously received an immune CPI (e.g., anti-programmed cell death ligand 1 (anti PD-L1), anti-programmed cell death 1 (anti-PD-1), anti-cytotoxic T lymphocyte-associated antigen 4 [CTLA-4]) prior to enrollment must have toxicities related to the CPI resolved to CTCAE ≤ Grade 1 or baseline (level prior to the CPI) to be eligible for enrollment. Patients who have experienced CPI-related endocrinopathies (e.g., diabetes, adrenal insufficiency) may participate if endocrinopathies are controlled (CTCAE ≤ Grade 1) with endocrinology support and appropriate repletion. Note: Patients who experienced previous hypothyroidism toxicity on a CPI are eligible to enter study regardless of CTCAE grade resolution as long as the patient is well controlled on thyroid replacement hormone.

Exclusion criteria

• Female patients who are pregnant or plan to become pregnant during the course of the trial
• Female patients who are breastfeeding
• Patients with symptomatic central nervous system (CNS) metastases must have been treated, be asymptomatic, and not have any of the following at the time of enrollment:

• Need for concurrent treatment for the CNS disease (e.g., surgery, radiation, corticosteroids >10 mg prednisone/day or equivalent)
• Progression of CNS metastases on CT or MRI for at least 28 days after last day of prior therapy for the CNS metastases
• Concurrent leptomeningeal disease or cord compression.
• Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is permitted.
• History of prior allogeneic bone marrow, stem-cell, or solid organ transplantation
• Treatment with any systemic anti-neoplastic therapy, or investigational therapy within the 14 days (or 28 days, for antibody drugs), before the first dose of CUE-102.
• Treatment with radiation therapy within 14 days before the first dose of CUE-102
• Treatment with corticosteroids (> 10 mg per day prednisone or equivalent) or other immune suppressive drugs within 14 days before the first dose of CUE-102. Steroids for topical, ophthalmic, inhaled, or nasal administration are permitted. Physiological replacement with up to a maximum dose of 5 mg equivalence of prednisone per day is permitted.
• History of clinically significant cardiovascular disease
• Clinically significant pulmonary compromise (e.g., requirement for supplemental oxygen)
• Clinically significant gastrointestinal (GI) disorders
• Patients who experienced the following immune CPI-related AEs are ineligible even if the AE resolved to ≤ Grade 1 or baseline:

• ≥ Grade 3 ocular AE
• Changes in liver function tests that met the criteria for Hy's Law (> 3× ULN of either ALT/AST with concurrent > 2× ULN of total bilirubin (total and direct) and without alternate etiology)
• ≥ Grade 3 neurologic toxicity
• ≥ Grade 3 colitis
• ≥ Grade 3 renal toxicity
• Evidence of active viral, bacterial, or systemic fungal infection requiring parenteral treatment within 7 days before the first dose of CUE-102.
• No known history of infection or positive test for HIV, Hepatitis B or Hepatitis C, testing prior to enrollment is not required unless mandated by local authority
• Second primary invasive malignancy that has not been in remission for > 2 years.
• History of trauma or major surgery within 28 days before the first dose of CUE-102
• Any serious underlying medical or psychiatric condition that would impair the ability of the patient to receive or tolerate the planned treatment at the investigational site
• Known hypersensitivity to recombinant proteins, polysorbate 80 or any excipient contained in the drug formulation for CUE-102
• Vaccination with any live virus vaccine within 28 days before the first dose of CUE-102. Inactivated annual influenza vaccination is allowed.
• Dementia or altered mental status that would preclude understanding and rendering of informed consent
• Active or history of significant alcohol or other substance abuse within 1 year before the first dose of CUE-102