FDA Grants Orphan Drug Designation to Fixed-Dose Senaparib/Temozolomide Combo for SCLC

The FDA has granted an orphan drug designation (ODD) to the fixed-dose combination capsule of the PARP inhibitor senaparib (IMP4297) and temozolomide for the treatment of adult patients with small cell lung cancer (SCLC), according to a press release from IMPACT Therapeutics.¹

“This is the first ODD [that] IMPACT [has] received from the FDA, which is a major development milestone for our company. This reflects efforts of our colleagues and collaborators. We shall take this as a further encouragement to our mission ‘Make IMPACT on Cancer Treatment’,” said IMPACT CEO Jun Bao, PhD.

Preliminary results from a phase 1b/2 dose-escalation and -expansion study (NCT04434482) presented during the 2022 ASCO Annual Meeting showed that 4 of 12 (33.3%) evaluable patients experienced objective responses including 3 confirmed partial responses (PRs). The disease control rate was 83.3% (n = 10), and the median duration of response was 3.6 months (range, 1.9-14.4). The median time to response was 7.3 months (range, 3.5-14.6). Two patients remained on treatment for more than 1 year.²

The median treatment duration in this population was 8.3 weeks (range, 2.1-86.1). The maximum tolerated dose and recommended phase 2 dose were determined to be 80 mg of senaparib once daily plus 20 mg once of temozolomide daily.

Senaparib is a novel and highly potent PARP1/2 inhibitor that has shown improved tolerability and a greater treatment window compared with other approved PARP inhibitors, and temozolomide is an orally available alkylating anti-tumor agent.In preclinical animal models, the combination of senaparib and temozolomide demonstrated evidence of synergistic anti-tumor activity without causing additive toxicity.

To be eligible for enrollment in part 1 of the global, open-label, multi-center study, adult patients with advanced solid tumors and SCLC had to be refractory to therapy or have no standard therapy available; and ECOG performance status of 0 or 1; adequate organ function; and no untreated or unstable brain metastases. Measurable lesions are not required.³

Patients with advanced solid tumors were enrolled for dose escalation to evaluate the safety and tolerability of the combination using a modified “3+3” design. Low-dose temozolomide (20 mg to 30 mg) was administered once daily on days 1 to 21 in combination with continuous senaparib (40 mg to 80 mg) once daily on days 1 to 28 of each 28-day cycle.

As of April 1, 2022, 14 patients with advanced solid tumors had been enrolled for dose escalation as follows: cohort 1 (n = 1; senaparib 40 mg plus temozolomide 20 mg), cohort 2 (n = 3; senaparib 60 mg plus temozolomide 20 mg), cohort 3 (n = 7; senaparib 80 mg plus temozolomide 20 mg), cohort 4 (n = 3; senaparib 80 mg plus temozolomide 30 mg). One dose-limiting toxicity of grade 4 thrombocytopenia was reported in cohorts 3 and 4.

A total of 14 patients with extensive-stage SCLC (ES-SCLC) following first-line treatment with platinum-based chemotherapy had been enrolled in part 2 as of the cutoff date. Eligible patients in part 2 had to be at least 18 years of age and have ES-SCLC; an ECOG performance status between 0 and 2; at least 1 measurable lesion; and no untreated or unstable brain metastases.

In this population, objective responses occurred in 3 of 7 (42.9%) evaluable patients, including 2 confirmed PRs in patients who remained on treatment. The median treatment duration was 7.4 weeks (range, 0.6-23.6) in this population, and the median time to response was 1.8 months (range, 1.7-1.9).2

Regarding safety, all adverse effects (AEs) were manageable, and no treatment-related deaths occurred.

In part 1, treatment-emergent AEs (TEAEs) occurred in 78.6% (n = 11) of patients, of which 57.1% (n = 8) were treatment-related. The most common TEAEs were anemia (n = 7), thrombocytopenia (n = 4), neutropenia (n = 3), fatigue (n = 3), nausea (n = 2), and pancytopenia (n = 1).

Grade 3 or greater TEAEs included anemia (n = 4), neutropenia (n = 3), thrombocytopenia (n = 3), and acute myocardial infarction (n = 1).

In part 2, TEAEs occurred in 64.3% (n = 9) of patients, the most common of which were anemia, thrombocytopenia, neutropenia, fatigue, and nausea. Six patients required dose reduction, and no patients discontinued treatment because of a TEAE.

Recruitment for part 2 is ongoing.

References

1. FDA granted orphan drug designation to IMP4297+TMZ for SCLC. News release. IMPACT Therapeutics. August 19, 2022. Accessed August 19, 2022. https://bit.ly/3PFlkro
2. Gao B, Lin CC, Bai LY, et al. A study of senaparib in combination with temozolomide for the treatment of patients with advanced solid tumors and extensive-stage small cell lung cancer. J Clin Oncol. 2022;40(suppl 16):3102. doi: 10.1200/JCO.2022.40.16_suppl.3102
3. IMP4297 in combination with temozolomide in patients with advanced solid tumors and small cell lung cancer. ClinicalTrials.gov. Updated August 17, 2021. Accessed August 19, 2022. https://clinicaltrials.gov/ct2/show/NCT04434482