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

Article

The FDA has granted an orphan drug designation to the fixed-dose combination capsule of the PARP inhibitor senaparib and temozolomide for the treatment of adult patients with small cell lung cancer.

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
Related Videos
A panel of 5 experts on lung cancer
A panel of 5 experts on lung cancer
Zofia Piotrowska, MD, MHS, and Martin Dietrich, MD, PhD, experts on lung cancer
Zofia Piotrowska, MD, MHS, and Martin Dietrich, MD, PhD, experts on lung cancer
Stephen V. Liu, MD
A panel of 5 experts on lung cancer
A panel of 5 experts on lung cancer
Millie Das, MD
A panel of 5 experts on lung cancer
A panel of 5 experts on lung cancer