Axatilimab in Combination with Retifanlimab and Paclitaxel for the Treatment of Patients with Advanced or Metastatic Solid Tumors

Inclusion Criteria

• Ability to comprehend the investigational nature of the study and provide informed consent. Written informed consent must be obtained prior to any study specific procedures or interventions
• Age ≥ 18 years at the time of consent. All participants, irrespective of their gender, gender identity, race, and ethnicity, will be included
• Certified, documented diagnosis of a metastatic solid tumor based on pathology review
• Presence of at least one lesion that is measurable per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and another lesion that is amenable to tumor biopsy
• Relapsed from, or refractory to, standard of care (SOC) systemic therapy known to prolong survival or if, in the opinion of the primary treating oncologist, a clinical trial is the best option for the next line of treatment based on response and/or tolerability to available therapies
• Investigational therapy is permitted after a wash-out period of 5 half-lives (if known), or 28 days, whichever is shorter, prior to study day -8. Prior use of an investigational agent for imaging, such as T cell imaging, is permitted
• Prior treatment with taxanes. A wash-out of period of ≥ 3 months prior to day -8 must be met for enrollment. Prior anti PD-1/PD-L1 therapy is allowed, but not required
• Eastern Cooperative Oncology Group (ECOG) status (performance status [PS]) of 0-1
• Life expectancy of greater than 12 weeks according to certified physician review
• Hemoglobin (Hb) ≥ 8.5 g/dL
• Leukocytes ≥ 3,000/mcL
• Absolute neutrophil count (ANC) ≥ 1,500/mcL
• Platelets ≥ 100K/cc mL * Values must be obtained without transfusion within 2 weeks
• Serum creatinine (sCr) < 1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl) ≥ 50 mL/min (calculated with the Cockcroft-Gault formula) for participants with creatinine (sCr) levels above institutional normal
• Total bilirubin < 1.5 x upper limit of normal (ULN) * With the exception of documented Gilbert’s syndrome or similar conditions, at the discretion of the principal investigator (PI). Clinical chemistry testing may be adjusted, as clinically indicated
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) or alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 x ULN
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association (NYHA) Functional Classification. To be eligible for this trial, patients should be class 2B or better
• Corrected QT interval Fridericia's formula (QTcF) of < 480 ms on a 12 lead electrocardiogram (EKG), except for participants with atrioventricular pacemakers or other conditions (e.g., right bundle branch block) that render the QT measurement invalid
• Willingness to modify concomitant drug regimens, at the recommendation and discretion of pharmacy services, including the use of known substrates or inhibitors of CYP2C8 and CYP3A4
• Physiologic maintenance doses of corticosteroids (≤ 10 mg/day of prednisone or equivalent) are permitted. Examples include: Asthma treatment; topical ocular, intra-articular, or intranasal steroids with minimal systemic absorption; and brief courses of corticosteroids for prophylaxis
• Patients with CD4+ T-cell (CD4+) counts ≥ 350 cells/uL are eligible regardless of HIV serology * HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of enrollment are eligible * In the case of ongoing treatment with antiretroviral therapy (ART), medication adjustment may be necessary for the duration of treatment. A wash-out period may be necessary, at the recommendation of the institutional research pharmacy service (RPS)
• Evidence of chronic hepatitis B virus (HBV) infection (i.e., hepatitis B surface antigen [HBsAg]-positive, undetectable or low HBV deoxyribonucleic acid [DNA], and normal ALT) in the absence of HBV therapy, or serologic evidence of a resolved prior HBV infection (i.e., HBsAg-negative and hepatitis B virus core antibody [anti-HBc]–positive) is permitted
• History of hepatitis C virus (HCV) infection is permitted given prior curative treatment or undetectable HCV viral load by serology or polymerase chain reaction (PCR) testing * Patient who are HCV antibody (Ab) seropositive but HCV ribonucleic acid (RNA) negative due to prior treatment or natural resolution are eligible

Exclusion Criteria

• Secondary malignancy with documented diagnosis by a treating physician < 3 years prior to study day -8. The following criteria also apply: * New or progressive brain metastases. Patients with brain metastases not requiring immediate central nervous system (CNS) specific treatment or stable for at least 4 weeks prior to study day -8 are eligible at the discretion of the investigator given that neurologic symptoms are resolved. * Patients with active leptomeningeal disease are not eligible
• Palliative radiation therapy administered within 1 week prior to study day -8, Note: Participants must have recovered from all radiation-related toxicities (to grade < 1 or baseline), must not require corticosteroids for this purpose, and must not have had radiation pneumonitis
• Immunization with a live vaccine within 28 days prior to study day -8
• History of organ transplantation, including hematopoietic stem cell transplantation (HSCT)
• Clinical evidence of interstitial lung disease or active non infectious pneumonia
• Active autoimmune disease requiring systemic immunosuppression in excess of physiologic maintenance doses of corticosteroids (≤ 10 mg/day of prednisone or equivalent is permitted)
• Prior National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 immune-related adverse event (irAE) that required systemic immunosuppression (endocrinopathies managed by stable doses of supplements and/or corticosteroids ≤ 10 mg/day are permitted)
• Unresolved toxicities (resolution required to grade 1 or baseline) from prior anticancer therapies. The following exceptions apply: * Alopecia, lymphopenia, grade 2 neuropathy (if not resulting in functional deficit), and grade 1 (no supplementation required) or grade 2 endocrinopathies (stable on supplements)
• Prior allergy or severe hypersensitivity reaction to axatilimab, retifanlimab, paclitaxel, cremaphor-containing agents, and/or components of the drug formulations
• Active infection requiring systemic antibiotic therapy
• Persons of childbearing potential (PCBP) who are pregnant (i.e., positive pregnancy test within 7 days prior to study day -8) or breastfeeding are not eligible. * The effects of the investigational regimen on the developing human fetus are unknown. For this reason, persons of reproductive potential must agree to use a highly effective form of contraception, starting with the time of consent to 4 months after the last dose of retifanlimab or 90 days after the last dose of axatilimab, whichever is longer * Sperm-producing participants must not donate sperm throughout the study period and for 90 days post completion of study treatment
• Uncontrolled, intercurrent illness and psychiatric illness/social situations that would limit compliance with study requirements, at the discretion of the investigator