ALX148 in Combination with Liposomal Doxorubicin and Pembrolizumab for the Treatment of Recurrent Platinum-Resistant Ovarian Cancer

Inclusion Criteria

• Participants must have recurrent epithelial ovarian cancer
• Platinum-resistant disease: Patients who recur within < 6 months of prior platinum-based therapy excluding those with primary platinum refractory disease
• Following histology types are acceptable: high grade serous or high grade endometrioid, clear cells, high grade translational cell, poorly differentiated or undifferentiated carcinomas, mixed histology (including one of above histology)
• 0–1 prior lines in platinum-resistant setting
• Known BRCA status or willing to be tested
• Up to 5 prior lines of therapy are allowed
• Participants must have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with at least one target lesion
• Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Participants must be female, age > 18 years. Because no dosing or adverse events (AE) data are currently available on the use of pembrolizumab in combination with ALX148 in participants =< 18 years of age, children are excluded from this study
• Hemoglobin >= 9.0 g/dL (may have been transfused) (within 14 days of enrollment unless otherwise indicated)
• Absolute neutrophil count >= 1,500/mcL (within 14 days of enrollment unless otherwise indicated)
• Platelet count >= 100,000/mcL (within 14 days of enrollment unless otherwise indicated)
• Total bilirubin =< 1.5 x the upper limit of normal (ULN) range (within 14 days of enrollment unless otherwise indicated)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X ULN or AST and ALT levels =< 5 x ULN (for participants with documented metastatic disease to the liver) (within 14 days of enrollment unless otherwise indicated)
• Estimated creatinine clearance >= 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method) (within 14 days of enrollment unless otherwise indicated)
• Thyroid-stimulating hormone (TSH) within normal institutional limits. If elevated, patient can be eligible if evaluated by an endocrine specialist, placed on replacement therapy and deemed eligible with no current or prior autoimmune disease (within 14 days of enrollment unless otherwise indicated)
• Participants must have the ability to understand and the willingness to sign a written informed consent document
• Negative serum or urine pregnancy test at screening for women of childbearing potential
• For pre-menopausal women with an intact uterus: willing to use highly effective contraception throughout the study and for at least months after last treatment administration if childbearing potential exists
• Availability of an archival formalin-fixed paraffin-embedded (FFPE) tumor tissue block from primary diagnosis specimen, metastatic, or recurrent site. If an FFPE tissue block cannot be provided then 15 unstained slides (10 microns, 10 slides minimum) will be acceptable

Exclusion Criteria

• Patients with sarcoma or carcinosarcoma or low-grade carcinoma
• Patients with primary platinum-refractory carcinoma who progressed while on or within 3 months of primary platinum-based combination therapy at first line setting
• Prior systemic anti-cancer therapy including investigational agents within 4 weeks [can be in follow-up phase of prior study and could consider shorter interval for kinase inhibitors or other short half-life drugs] prior to [randomization /allocation]. * Note: Participants must have recovered from all AEs due to previous therapies to =< grade 1 or baseline. Participants with =< grade 2 neuropathy may be eligible. Participants with endocrine-related AEs grade =< 2 requiring treatment or hormone replacement may be eligible. * Note: If the participant had major surgery, the participant must have recovered adequately from the procedure and/or any complications from the surgery prior to starting study intervention
• Prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation ( =< 2 weeks of radiotherapy) to non-central nervous system (CNS) disease
• Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention
• Known symptomatic brain metastases requiring steroids. Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study enrollment, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable with no evidence of disease progression for 3 months
• Patients having received prior therapy with PD1, PDL1, CTLA4 inhibitors, CD47 or SIRP1- alpha inhibitors or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137), or other immunotherapeutic agents
• Prior therapy with PLD. Patients who received PLD in combination with platinum in platinum sensitive setting are allowed if they had initial objective complete response and PLD-platinum free interval of 6 months or more
• Active autoimmune disease that might deteriorate when receiving an immune-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed
• Patients currently on immunosuppressive therapy except: * Intra-nasal, inhaled, topical or local steroid injections (e.g., intra-articular injection) * Steroids as premedication for hypersensitivity reaction (e.g., CT scan premedication). * Systemic corticosteroids at physiologic doses not exceeding 10 mg/day of prednisone or equivalent
• Patients who are pregnant or breast feeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment
• Known history of immune-mediated colitis, inflammatory bowel disease, pneumonitis ([non-infectious] pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease), pulmonary fibrosis
• Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (>= New York Heart Association Classification class II), or serious cardiac arrhythmia requiring medication
• Individuals with a history of a different malignancy are ineligible except for the following circumstances: Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed and underwent potentially curative therapy: breast cancer in situ, cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin. Patients with a history of carcinoma in situ of the bladder are excluded
• Prior organ transplantation including allogenic stem-cell transplantation
• Active infection requiring intravenous systemic therapy. Oral antibiotic therapy is allowed
• Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as HCV ribonucleic acid [RNA] [qualitative] is detected) infection. * Note: no testing for hepatitis B and hepatitis C is required unless mandated by local health authority or treating physician per standard of care except ** Patients with a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection are allowed to be included if: participant on a stable dose of antiviral therapy, hepatitis B virus (HBV) viral load below the limit of quantification. HCV viral load below the limit of quantification
• History of infection with (screening tests not required) human immunodeficiency virus; except following situation: * Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of enrollment are eligible for this trial
• Received live or live-attenuated vaccine within 4 weeks of the first dose of treatment and while on trials is prohibited except for administration of inactivated vaccines. Influenza and human coronavirus 2019 infection (COVID) vaccinations are permissible
• Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version [v]5 grade >= 3)
• Persistent toxicity related to prior therapy (NCI CTCAE v. 5 grade > 1); however, alopecia, sensory neuropathy grade =< 2, or other grade =< 2 not constituting a safety risk based on investigator's judgment are acceptable
• Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration 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
• A woman of child bearing potential (WOCBP) who has a positive urine pregnancy test within 72 hours prior to randomization/allocation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required