Salarius Pharmaceuticals has voluntarily paused enrollment of new patients into a phase 1/2 trial (NCT03600649) investigating seclidemstat (SP-2577) in patients with Ewing sarcoma, sarcomas with 

-family translocations, and myxoid liposarcoma due to the death of a patient.

The death of the patient with metastatic 

-rearranged sarcoma has been classified as a suspected unexpected serious adverse reaction (SUSAR). Salarius has submitted details to the FDA and aims to understand how to proceed and restart enrollment as soon as possible.

Following a review by an independent safety review committee for the clinical trial, patients currently receiving seclidemstat may continue treatment after consulting with their physician.

“Patient safety is our primary concern, and this is reflected in the design of our clinical trial protocol, which automatically paused enrollment based upon this SUSAR,” David Arthur, chief executive officer of Salarius, stated in a press release. “Unfortunately, pauses to enrollment occur in early-stage drug development, but these pauses allow time to understand new data and adjust clinical protocols and development plans as needed. We plan to restart enrollment as soon as possible.”

the FDA granted fast track designation to seclidemstat for the treatment of relapsed/refractory patients with Ewing sarcoma

The phase 1/2 trial enrolled patients at least 12 years of age and weighing at least 40 kg who had Ewing sarcoma, myxoid liposarcoma, or 

 All patients were required to have a Karnofsky performance status of at least 70% for over those who were at least 16 years old or a Lansky performance status of at least 70% for those under 16 years old. Patients also needed to have a life expectancy of more than 4 months, plus adequate bone marrow and organ function.

Those with Ewing sarcoma were required to have a histologic confirmed diagnosis of Ewing sarcoma with a known 

 translocation through local assessment that is relapsed or refractory after at least one prior course of therapy for Ewing sarcoma. Patients must have had no more than 2 lines of systemic treatment for Ewing sarcoma, and no prior therapy with the combination regimen of topotecan and cyclophosphamide was permitted. Prior cyclophosphamide is allowed if not combined with topotecan.

Patients enrolled in the myxoid liposarcoma cohort or the 

-translocated sarcoma cohort needed to have a histologic confirmed diagnosis of one of the sarcomas that share similar known chromosomal translocations to Ewing sarcoma. Patients needed to be relapsed or refractory and not amenable to surgery at time of enrollment. Between 1 and 3 courses of prior systemic therapy for sarcoma was required.

Enrolled patients with Ewing sarcoma received a twice-daily administration of seclidemstat in combination with cyclophosphamide and topotecan. Those in the myxoid liposarcoma cohort or the 

-translocated sarcoma cohort were given a twice-daily administration of seclidemstat alone.

The primary end point of the trial is the safety and tolerability of treatment with seclidemstat. Establishing the maximum tolerated dose of seclidemstat, pharmacokinetics, and antitumor activity serve as secondary end points.

Despite the voluntary enrollment pause, Salarius plans to release interim clinical trial results later in 2022.

Salarius Pharmaceuticals announces pause in new patient enrollment in its phase 1/2 trial of seclidemstat in Ewing sarcoma and FET-rearranged sarcoma. News release. Salarius Pharmaceuticals. October 18, 2022. Accessed October 19, 2022. 

Salarius Pharmaceuticals receives FDA fast track designation for lead drug candidate, seclidemstat, in relapsed or refractory Ewing sarcoma. News release. Salarius Pharmaceuticals. December 16, 2019. Accessed October 19, 2022. 

Clinical trial of SP-2577 (seclidemstat) in patients with relapsed or refractory Ewing or Ewing-related sarcomas. ClinicalTrials.gov. Updated August 25, 2022. Accessed October 19, 2022. 

https://clinicaltrials.gov/ct2/show/NCT03600649

Articles

Salarius Pharmaceuticals has voluntarily paused enrollment of new patients into a phase 1/2 trial investigating seclidemstat in patients with Ewing sarcoma, sarcomas with FET-family translocations, and myxoid liposarcoma due to the death of a patient.

Salarius Pauses Phase 1/2 Trial Investigating Seclidemstat in Ewing Sarcoma and FET-Rearranged Sarcomas Following Death

The targeted radiotherapy candidate lutetium-177-FAP-2286 (

Lu-FAP-2286) produced preliminary evidence of antitumor activity with a manageable safety profile in patients with advanced or metastatic solid tumors, according to data from the phase 1/2 LuMIERE trial (NCT04939610) presented at the 

Lu-FAP-2286 up to 7.4 GBq, 1 (9.1%) patient achieved a confirmed partial response and completed 6 doses of 

Lu-FAP-2286 at 3.7 GBq. This patient has continued without disease progression or subsequent anticancer therapy more than 12 months after the first dose of 

Lu-FAP-2286. Additionally, 1 heavily pretreated patient in the 5.55 GBq cohort experienced stable disease.

“The LuMIERE trial is the first prospective trial of a FAP peptide targeted radionuclide therapy and is currently in the dose-escalation phase. To date we have not seen evidence of significant associated toxicities that would limit therapy, and have seen some evidence of early efficacy,” Thomas A. Hope, MD, director of Molecular Therapy in the Department of Radiology and Biomedical Imaging at the University of California, San Francisco, and principal investigator of the LuMIERE trial, stated in a press release.

“We are excited about these results and the fact that FAP is expressed across a number of tumor types, and we look forward to seeing the future results.”

Lu-FAP-2286 include a targeting peptide that binds to FAP and a site that can be used to attach radioactive isotopes for imaging and therapeutic use. Malignancies such as pancreatic ductal adenocarcinoma, unknown primary cancer, salivary gland cancer, mesothelioma, colon cancer, bladder cancer, sarcoma, squamous non–small cell lung cancer, and head and neck squamous cell carcinoma (HNSCC) have been associated with high FAP expression.

LuMIERE enrolled patients who were at least 18 years old with refractory or progressive advanced/metastatic solid tumors following prior treatment who had no satisfactory alternative treatment options. Patients were required to have measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, adequate organ function, and a life expectancy of at least 6 months. No prior systemic radionuclide therapy was permitted.

Prior to treatment, investigators conducted PET/CT scans with 

Ga-FAP-2286 to select patients for treatment with 

Lu-FAP-2286. The dose-escalation portion of the trial was designed to enroll up to 30 patients to receive 

Lu-FAP-2286 at doses of 3.7 GBq (100 mCi), 5.55 GBq (150 mCi), 7.4 GBq (200 mCi), or 9.25 GBq (250 mCi). Enrollment is ongoing at dose level 3 of 7.4 GBq. 

Lu-FAP-2286 was administered on day 1 of each 6-week cycle for up to 6 cycles.

The primary end points of the trial were to evaluate the safety and tolerability of 

Lu-FAP-2286 and to determine the recommended phase 2 dose and treatment schedule. Secondary end points were to measure the radiation dosimetry of 

Lu-FAP-2286, evaluate the preliminary efficacy of 

Lu-FAP-2286, determine the tumor uptake using 

The median age of enrolled patients was 64 years (range, 27-71), 36.4% were female, 45.5% were White, 36.4% were Black or African American, and 45.5% had an ECOG performance status of 0. Tumor and histology type included colorectal adenocarcinoma (n = 3), pancreatic ductal adenocarcinoma (n = 2), and 1 each for adenoid cystic carcinoma, gallbladder adenocarcinoma, HNSCC, neuroblastoma, pseudomyxoma peritonei of appendiceal origin, and soft-tissue sarcoma desmoplastic small round cell tumor. All patients received at least 3 prior anticancer therapies.

Regarding safety, 90.9% of patients experienced at least 1 treatment-emergent adverse effect (TEAE) of any grade, and 45.5% experienced a grade 3 or higher TEAE. The most common any-grade TEAEs included fatigue (45.5%), anemia (27.3%), arthralgia (27.3%), abdominal distension (18.2%), back pain (18.2%), constipation (18.2%), and diarrhea (18.2%). Investigators observed 1 event each of grade 3 or higher abdominal distension, cholangitis, hyponatremia, increased blood bilirubin, lymphopenia, and spinal compression fracture.

One instance of grade 4 lymphopenia related to the study drug was reported in 1 patient in the 5.55 GBq cohort and was considered a dose-limiting toxicity. There were no serious AEs observed, and treatment did not lead to any discontinuations.

“This presentation of updated data from the phase 1/2 LuMIERE study continues to support the hypothesis that 

Lu-FAP-2286 gets to the tumor, stays in the tumor, and avoids off-target tissue. These initial phase 1 data further support the potential clinical utility of 

Lu-FAP-2286 as a targeted radionuclide therapy to treat a variety of advanced solid tumors,” Patrick J. Mahay, president and chief executive officer of Clovis Oncology, stated in a press release. “We anticipate additional clinical data from the LuMIERE study to be presented at a medical conference in the first quarter of 2023.”

Clovis Oncology highlights updated LuMIERE phase 1 data of targeted radiotherapy candidate FAP-2286 at the 35th Annual EANM Congress. News release. Clovis Oncology. October 17, 2022. Accessed October 18, 2022. 

Lu-FAP-2286 in patients with advanced or metastatic solid tumors: updated data from a phase 1/2 study investigating safety, pharmacokinetics, dosimetry, and preliminary antitumor activity (LuMIERE). Presented at: 35th Annual EANM Congress; October 15-19, 2022; Barcelona, Spain. Abstract OP-355. 

Lutetium-177-FAP-2286 produced preliminary evidence of antitumor activity with a manageable safety profile in patients with advanced or metastatic solid tumors, according to data from the phase 1/2 LuMIERE trial.

177Lu-FAP-2286 Displays Preliminary Antitumor Activity in Advanced or Metastatic Solid Tumors

The therapeutic DNA vaccine, GX-188E, in combination with pembrolizumab (Keytruda) produced encouraging responses in patients with human papillomavirus (HPV) 16- or 18-positive, recurrent or metastatic cervical cancer who did not respond to standard-of-care treatment, according to data from an ongoing phase 1b/2 trial (NCT03444376).

In the 60 patients who comprised the efficacy set, the combination regimen elicited an objective response rate (ORR) of 31.7% (95% CI, 20.3%-45.0%), which was comprised of a complete response rate of 10.0%, a partial response rate of 21.7%, and a stable disease rate of 16.7%. Moreover, 51.7% of patients experienced disease progression. The disease control rate (DCR) in this population was 48.3% (95% CI, 35.2%-61.6%).

Among the 19 patients who responded to treatment, the median duration of response (DOR) was 12.3 months (95% CI, 7.8-16.9). The median progression-free survival (PFS) with the regimen was 3.0 months (95% CI, 0.3-5.8), and the median overall survival (OS) was 17.2 months (95% CI, 6.6-27.8).

“[The regimen] was safe and tolerable—comparable to pembrolizumab monotherapy,” lead study author Sung-Jong Lee, PhD, MS, of the Catholic University of Korea, Seoul St. Mary’s Hospital, Seocho-gu, Seoul, Korea, said in a presentation on the data delivered at the 2022 ESMO Congress. “A phase 3 clinical trial is warranted based on [the] promising efficacy and safety [observed] in this trial.”

The open-label, early-phase trial enrolled previously treated patients with recurrent, persistent, and metastatic cervical cancer who had measurable disease by RECIST v1.1 criteria, HPV 16 or 18 positivity, an ECOG performance status of 0 or 1, and a life expectancy of at least 6 months.

A total of 65 patients were enrolled to the trial, and they were vaccinated with GX-188E at 2 mg intramuscularly at weeks 1, 2, 4, 7, 13, and 19. Patients were also intravenously administered pembrolizumab at 200 mg every 3 weeks.

Participants underwent a tumor assessment at 10 weeks; they were evaluated every 9 weeks thereafter. Four weeks after disease progression, a confirmatory assessment was conducted.

ORR by RECIST v1.1 criteria served as the primary objective for the research. Key secondary objectives included DCR, DOR, PFS, OS, and safety. Exploratory objectives comprised T-cell response analysis, as well as evaluation of biomarkers such as PD-L1, CEA, TA4, and others.

The median age of the 65 patients who received treatment was 53 years (range, 27-79). Most patients (60.0%) had a PD-L1 combined positive score (CPS) of 1 or more, the remainder had negative status. Moreover, 49.2% of patients had an ECOG performance status of 0, and 50.8% had a status of 1. Regarding HPV type, 75.4% had HPV 16, 23.1% had HPV 18, and 1.5% had both. Most patients (76.9%) had squamous cell carcinoma (SCC), but the remaining 23.1% of patients had adenocarcinoma (AC). The number of prior lines of adjuvant and/or neoadjuvant treatment received was 3, with 44.6% of patients having received 1 line, 35.4% having received 2 lines, and 15.4% having received 3 or more lines.

Additional data showed that the combination produced relatively higher ORRs in those with PD-L1 positivity and those with SCC.

The regimen induced an ORR of 36.1% (95% CI, 20.8%-53.8%) in those with PD-L1–positive status (n = 36) vs 25.0% (95% CI, 9.8%-46.7%) in those with negative status (n = 24); the CBRs in these groups were 55.6% (95% CI, 38.1%-72.1%) and 37.5% (95% CI, 18.8%-59.4%), respectively.

Among those who responded, those with PD-L1 positivity (n = 13) experienced a median DOR of 12.3 months vs 14.4 months in those with negative status (n = 6). In the PD-L1–positive group, the median PFS was 4.4 months and the median OS was 23.8 months. In the PD-L1–negative group, the median PFS and OS were 2.1 months and 14.0 months, respectively.

In those with HPV16 (n = 45), the ORR achieved with the regimen was 31.1% (95% CI, 18.2%-46.6%) vs 33.3% (95% CI, 11.8%-61.6%) in those with HPV18 or both (n = 15); the CBRs in these groups were 48.9% (95% CI, 33.7%-64.2%) and 46.7% (95% CI, 21.3%-73.4%), respectively. In those with SCC (n = 46) and AC (n = 14), the ORRs were 32.6% (95% CI, 19.5%-48.0%) and 28.6% (95% CI, 8.4%-58.1%), respectively; the DCRs were 50.0% (95% CI, 34.9%-65.1%) and 42.9% (95% CI, 17.7%-71.1%), respectively.

Regarding safety, any-grade treatment-related adverse effects (TRAEs) were reported in 33.8% of patients; these effects were grade 3 in 4.6% of patients and grade 4 in 1.5% of patients.

The most common TRAEs experienced with the combination regimen were hypothyroidism (13.8%), diarrhea (3.1%), nausea (3.1%), vomiting (3.1%), urticaria (3.1%), increased alanine and aspartate (AST) aminotransferase (3.1% each), increased TSH (3.1%), thyroiditis (1.5%), gastrointestinal pain (1.5%), oral mucositis (1.5%), pruritus (1.5%), rash (1.5%), xerotic eczema (1.5%), increased T3 (1.5%), decreased neutrophil count (1.5%), back pain (1.5%), myalgia (1.5%), extremity pain (1.5%), syncope (1.5%), dizziness (1.5%), and peripheral sensory neuropathy (1.5%).

Grade 3 TRAEs included increased AST (1.5%), decreased neutrophil count (1.5%), and syncope (1.5%). Only 1 grade 4 TRAE of increased ALT was reported.

“Overall, GX-188E combined with pembrolizumab was safe and tolerable,” Lee said.

Lee S, Lim M-C, Kim YM, et al. Efficacy and safety of GX-188E, a therapeutic DNA vaccine, combined with pembrolizumab in HPV 16- and/or 18-positive advanced cervical cancer (phase II): safe and effective in both PD-L1 positive and negative. 

. 2022;33(suppl 7):S1398. doi:10.1016/j.annonc.2022.08.028

The therapeutic DNA vaccine, GX-188E, in combination with pembrolizumab produced encouraging responses in patients with human papillomavirus 16- or 18-positive, recurrent or metastatic cervical cancer who did not respond to standard-of-care treatment.

Pipeline Report: October 2022

Articles

Salarius Pauses Phase 1/2 Trial Investigating Seclidemstat in Ewing Sarcoma and FET-Rearranged Sarcomas Following Death

177Lu-FAP-2286 Displays Preliminary Antitumor Activity in Advanced or Metastatic Solid Tumors