SL-17154 Appears Promising, Tolerable in Treatment of Platinum-Resistant Ovarian Cancer
In a phase 1 dose-escalation trial, treatment with the investigative agent was well tolerated with no dose-limiting toxicities.
Patients with platinum-resistant ovarian cancer responded favorably to the investigative agent SL-172154 (SIRPα-Fc-CD40L) in a phase 1 dose-escalation trial. Findings from the study, which were presented during the 2021 SITC Annual Meeting, revealed that the agent was well tolerated and that there were no observed dose-limiting toxicities (DLTs).
Results showed that among 14 patients who were evaluable for efficacy and had undergone a post-baseline scan, the hexameric bifunctional fusion protein resulted in a best response of stable disease in 4 patients. Nine patients experienced disease progression. Moreover, 1 patient was determined to be not evaluable, as they were considered to have stable disease, but they did not meet the protocol-specified minimum interval for disease stability.
“SL-172154 was well tolerated with no DLTs or evidence of anemia, thrombocytopenia, liver dysfunction, cytokine release syndrome, or pneumonitis,” Nehal Lakhani, MD, PhD, lead study author and director of clinical research at START Midwest, and colleagues, wrote in the poster. “Preliminary pharmacokinetic [PK] parameters for SL-172154 suggest target-mediated drug disposition via receptor binding. High receptor occupancy was observed for [the agent] on CD47-positive leukocytes at the doses studied, with minimal binding to red blood cells [RBCs].”
SL-172154 was developed using an Agonist Redirected Checkpoint platform, which connects the extracellular domain of a type 1 membrane protein to the domain of a type 2 membrane protein through a central Fc domain derived from an IgG4 antibody. The bifunctional proteins are designed to block the tumor cells from transmitting an immune inhibitory signal, as they concurrently deliver an immune stimulatory signal to immune cells in the tumor microenvironment.
SL-172154 is comprised of SIRPα, which has a binding affinity to CD47 of 0.628 nM, linked to CD40L, which has a binding affinity to CD40 of 4.74 nM, through an Fc linker protein. The agent was developed to bridge innate and adaptive immunity by strengthening tumor cell phagocytosis and antigen cross-presentation to CD8 T cells.
In preclinical studies, the agent resulted in higher rates of tumor rejection and long-term immunity than CD47-blocking antibodies, CD40 agonist antibodies, or a combination comprised of these 2 modalities.
In the first-in-human phase 1 trial, investigators set out to evaluate single-agent SL-172154 in patients with locally advanced or metastatic ovarian cancer, primary peritoneal cancer, or fallopian tube cancer who were refractory to existing therapies or ineligible to receive further platinum-based treatment.
To be eligible for enrollment, patients needed to be at least 18 years of age, have an ECOG performance status of 0 or 1, and measurable disease per RECIST v1.1 criteria. Patients who were positive for homologous recombination deficiency must have previously received a PARP inhibitor with or without bevacizumab (Avastin).
If patients had primary platinum-refractory disease, or received previous treatment with an anti-CD47, anti-SIRPα targeting agent, or a CD40 agonist, they were excluded. Patients with a documented history of autoimmune disease or active pneumonitis, or who required concurrent use of systemic corticosteroids or other immunosuppressive medications, were also excluded.
The planned dose-escalation for the trial was in half-log increments. The agent was given at the following doses: level 1 was 0.1 mg/kg (n = 3), level 2 was 0.3 mg/kg (n = 3), level 3 was 1.0 mg/kg (n = 3), level 4 was 3.0 mg/kg (n = 3), and level 5 was 10.0 mg/kg.
Those receiving schedule 1 escalated from dose level 1 to 2, and those receiving schedule 2 escalated from dose level 2 to dose level 5. Those on schedule 1 received the agent on day 1, 8, and 15 and then every 2 weeks of each 28-day treatment cycle. Those on schedule 2 received the drug on day 1, 8, 15, and 22 once weekly of each 28-day cycle.
At least 3 patients were enrolled to sequential dose levels and evaluated for DLTs in the first treatment cycle. Patients received intravenous (IL) SL-172154 on schedule 1 or 2. Treatment was administered until progressive disease, intolerable toxicity, or withdrawn consent. Patients are currently being enrolled to receive the agent at dose level 5.
The primary objective of the research was to assess for safety and identify the maximum tolerated dose of SL-172154. Secondary objectives included identifying the recommended phase 2 dose, characterizing the PK and immunogenicity of the agent, and evaluating antitumor activity per RECIST v1.1 criteria for solid tumors. Exploratory objectives comprised assessment of receptor occupancy of SIRPα and CD40 on peripheral blood mononuclear cells and investigation of pharmacodynamic (PD) effects in the blood and tumor tissue.
At a data cutoff of September 15, 2021, a total of 15 patients were enrolled; these patients had received a median of 5 prior lines of systemic therapy (range, 2-7) and were given IV SL-172154 across 4 dose levels on 2 schedules. Six patients received treatment on schedule 1, and 9 received treatment on schedule 2.
The median age of participants was 67 years (range, 33-79). Sixty percent of patients had ovarian cancer, 27% had primary peritoneal cancer, and 13% had fallopian tube cancer. Moreover, 60% had FIGO stage IV disease, and the remainder had stage III disease. Most patients (73%) had high-grade disease. Regarding histology, 73% had serous carcinoma, 13% had adenocarcinoma, and 13% had serous adenocarcinoma. Thirteen patients had an ECOG performance status of 1 at baseline.
Additional PK data from the trial showed that Cmax and AUCinf increased disproportionately as the dose of the agent increased. Clearance decreases were also observed with increasing doses. Moreover, the PK appeared to be biphasic at 1.0 mg/kg and 3.0 mg/kg, according to the study authors. However, the elimination phase of the curve was not fully characterized at the doses evaluated.
SL-172154 was also found to stimulate reproducible increases in serum cytokines after repeated dosing, and the agent also stimulated dose-dependent and reproducible increases in serum IL-12. Moreover, the agent was also noted to preferentially bind CD47 on leukocytes, but not RBCs. The drug stimulated dose-dependent B-cell margination and activation.
Regarding safety, all 15 patients experienced any-grade adverse effects (AEs). Toxicities included fatigue (60%), infusion-related reactions (IRRs; 53%), nausea (33%), diarrhea (27%), decreased appetite (20%), dehydration (20%), pruritus (20%), abdominal distention (13%), back pain (13%), chills (13%), constipation (13%), dyspnea (13%), hypomagnesemia (13%), injection site reactions (13%), and vomiting (13%).
Three grade 3 AEs were reported and included sepsis, embolism, and IRR, although these toxicities were not determined to be associated with the study drug. No grade 4 or 5 toxicities were observed.
Ninety-three percent of patients experienced treatment-related AEs (TRAEs), which comprised IRR (53%), fatigue (47%), nausea (27%), decreased appetite (20%), chills (13%), diarrhea (13%), and dyspnea (13%). No grade 3 or higher TRAEs were experienced.
Fifty-three percent of patients experienced IRRs; this included 3 patients who received the agent at a dose of 0.3 mg/kg, 2 who received it at a dose of 1.0 mg/kg, and 3 who received it at a dose of 3.0 mg/kg. One of these effects was grade 3 in severity and was determined to be secondary to iron infusion. Fourteen IRRs were grade 2 and 2 were grade 1. These effects were noted to be manageable with pre-medications and did not prevent the completion of dosing or result in discontinuation.
Notably, no DLTs were reported with SL-172154 on either schedule, with doses ranging from 0.1 mg/kg to 3.0 mg/kg.
Eighty-seven percent of patients discontinued treatment with the agent; 12 of the 13 patients discontinued because of radiological or clinical progression and 1 patient chose to stop treatment.
“SL-172154 has been well-tolerated at doses which saturate both CD40 and CD47, with evidence of on-target PD activity which has not yet plateaued, warranting further dose escalation,” the study authors concluded.
Lakhani NJ, Richardson D, Kristedja T, et al. Phase 1 dose escalation study of the agonist redirected checkpoint, SL-172154 (SIRPα-Fc-CD40L) in subjects with platinum-resistant ovarian cancer. Presented at: 2021 SITC Annual Meeting; November 10-14, 2021; Washington DC. Abstract 429.
This article was originally published on OncLive as “SL-172154 Shows Favorable Tolerability in Platinum-Resistant Ovarian Cancer”