FDA Grants Fast Track Status to CX-5461 for Breast and Ovarian Cancers With BRCA1/2, PALB2, or Other HRD Mutations

January 25, 2022

The FDA has granted a fast track designation to CX-5461 (Pidnarulex) as a potential therapeutic option for patients with breast and ovarian cancers that harbor BRCA1/2, PALB2, or other homologous recombination deficiency mutations.

The FDA has granted a fast track designation to CX-5461 (Pidnarulex) as a potential therapeutic option for patients with breast and ovarian cancers that harbor BRCA1/2, PALB2, or other homologous recombination deficiency mutations.¹

A G4-stablizing compound, CX-5461 was designed to stabilize folded conformation, and act in tandem with HR pathway deficiency; this stalls replication forks from undergoing DNA breaks and results in cancer death.² Stabilization of G4 at the replication fork can lead to significant genomic instability and DNA breaks.

In HRD cancers, there is a deficiency in the ability of cells to repair themselves, which means that these cancers carry a high load of DNA mutations are genomically unstable. By targeting DNA repair defects in HRD tumors, CX-5461 represents a synthetic lethality approach and is supplied as a lyophilized drug with intravenous administration.

“We are excited to receive fast track designation and look forward to working closely with the FDA to accelerate the development of Pidnarulex, aiming to bring a meaningful treatment to patients with breast and ovarian cancer whose tumors have BRCA1/2, PALB2, or other HRD mutations,” Mei-Hui Kuo, acting chief executive officer of Senhwa Biosciences, stated in a press release.

Previously, results from a phase 1 trial (NCT02719977) showed that treatment with the agent resulted in clinically significant and durable benefits in patients with BRCA1/2 and PALB2 mutations who were also resistant to platinum and other chemotherapies.

CX-5461 is currently under investigation in an open-label, multicenter phase 1b trial (NCT04890613), which seeks to determine a tolerable dose of the agent in patients with select solid tumors and associated mutations for future clinical research.³

To be eligible for enrollment, patients must be at least 18 years of age, have an ECOG performance status of 0 to 2, radiographically documented progressive disease, and acceptable bone marrow, renal, and hepatic function. Patients also need to have a life expectancy of greater than 3 months.

To be included in the main study cohort, patients must have a histologically or cytologically confirmed malignancy of the pancreas, prostate, breast, or ovary and documented evidence of a BRCA2 and/or PALB2mutation; they must also have measurable disease per RECIST v1.1 criteria.

The exploratory cohort of the trial will be comprised of those with histologically confirmed ovarian, fallopian tube, or primary peritoneal cancer, with a high grade serous or high-grade endometroid histology subtype. These patients will need to have documented evidence of a BRCA1 and/or other HRD-associated mutation, and measurable disease. They will also need to be platinum sensitive with no evidence of disease progression within 6 months of their last dose of platinum-based chemotherapy, or they need to be platinum resistant with disease progression within 6 months of their last dose of platinum-based treatment.

The trial is estimated to enroll 52 patients total, with 32 included in the main study cohort and 20 patients included in the exploratory cohort.

Study participants in the main or exploratory cohorts will receive CX-5461 at a dosing concentration of either 250 mg/m2 or 325 mg/m2, administered as an intravenous infusion over the course of 60 minutes on days 1 and 8 of a 28-day treatment cycle.

The primary objective is to identify the recommended phase 2 dose of CX-5461, and the key secondary objectives are to evaluate the safety and tolerability of the agent, assess the antitumor activity of the patients in those with solid tumors and germline BRCA2 and/or PALB2 alterations, and to examine the effect of the agent on health-related quality of life.⁴

Exploratory objectives include evaluating the antitumor activity of the agent in patients with ovarian cancer and pathogenic/suspected pathogenic BRCA1 mutation and/or other HRD-associated somatic mutations, to characterize the molecular profile of the cancers and examine the predictive value of mutational signatures in terms of response or resistance to CX-5461, and to assess the significance of dynamic changes in circulating tumor DNA levels and plasma DNA.

The safety, pharmacokinetics, and pharmacodynamics of CX-5491 was also under evaluation in patients with advanced hematologic malignancies as part of an open-label, dose-escalation phase 1 trial (ACTRN12613001061729).⁵

References

Senhwa’s Pidnarulex receives US FDA fast track designation for the treatment of solid tumors with BRCA1/2, PALB2 and other HR gene mutations. News release. Senhwa Biosciences, Inc.; January 24, 2022. Accessed January 25, 2022. https://bit.ly/3FUAKTS
Pidnarulex (CX-5461): G-quadruplex (stabilizer). Senhwa Biosciences, Inc. website. Accessed January 25, 2022. https://bit.ly/3H47kUy
Study of CX-5461 in patients with solid tumors and BRCA1/2, PALB2 or homologous recombination deficiency (HRD) mutation. ClinicalTrials.gov. Updated January 5, 2022. Accessed January 25, 2022. https://clinicaltrials.gov/ct2/show/NCT04890613
CX-5461-solid tumors and BRCA2 and/or PALB2 mutation. Senhwa Biosciences, Inc. website. Accessed January 25, 2022. https://bit.ly/3H3Q4Pt
ACTRN12613001061729. Australian New Zealand Clinical Trials Registry. Updated September 23, 2013. Accessed January 25, 2022. https://bit.ly/3Aythc3