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A Phase 1 Study of the DNA-PK Inhibitor Peposertib in Combination With Radiation Therapy With or Without Cisplatin in
Michael Samuels1, Johan Falkenius2, Voichita Bar-Ad3
1"Banner MD Anderson Cancer Center, Phoenix, Arizona, USA.
Purpose:
DNA-dependent protein kinase (DNA-PK) plays a key role in the repair of DNA double strand breaks via nonhomologous end joining. Inhibition of DNA-PK can enhance the effect of DNA double strand break inducing anticancer therapies. Peposertib (formerly "M3814") is an orally administered, potent, and selective small molecule DNA-PK inhibitor that has demonstrated radiosensitizing and antitumor activity in xenograft models and was well-tolerated in monotherapy. This phase 1 trial (National Clinical Trial 02516813) investigated the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, and tolerability of peposertib in combination with palliative radiation therapy (RT) in patients with thoracic or head and neck tumors (arm A) and of peposertib in combination with cisplatin and curative-intent RT in patients with squamous cell carcinoma of the head and neck (arm B).
Methods And Materials:
Patients received peposertib once daily in ascending dose cohorts as a tablet or capsule in combination with palliative RT (arm A) or in combination with intensity modulated curative-intent RT and cisplatin (arm B).
Results:
The most frequently observed treatment-emergent adverse events were radiation skin injury, fatigue, and nausea in arm A (n = 34) and stomatitis, nausea, radiation skin injury, and dysgeusia in arm B (n = 11). Based on evaluations of dose-limiting toxicities, tolerability, and pharmacokinetic data, RP2D for arm A was declared as 200 mg peposertib tablet once daily in combination with RT. In arm B (n = 11), 50 mg peposertib was declared tolerable in combination with curative-intent RT and cisplatin. However, enrollment was discontinued because of insufficient exposure at that dose, and the RP2D was not formally declared.
Conclusions:
Peposertib in combination with palliative RT was well-tolerated up to doses of 200 mg once daily as tablet with each RT fraction. When combined with RT and cisplatin, a tolerable peposertib dose yielded insufficient exposure.
Insights
The DNA-dependent protein kinase (DNA-PK) inhibitor peposertib showed good tolerability with palliative radiation therapy (RT) up to 200 mg daily. However, combining peposertib with RT and cisplatin resulted in insufficient exposure.
Area of Science:
- Oncology
- Radiation Oncology
- Pharmacology
Background:
- DNA-dependent protein kinase (DNA-PK) is crucial for DNA double-strand break repair via nonhomologous end joining.
- Inhibiting DNA-PK can potentiate anticancer therapies that induce DNA double-strand breaks.
- Peposertib (M3814) is an oral, potent, selective DNA-PK inhibitor with demonstrated radiosensitizing and antitumor effects in preclinical models.
Purpose of the Study:
- To investigate the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety, and tolerability of peposertib.
- To evaluate peposertib in combination with palliative radiation therapy (RT) for thoracic or head/neck tumors (Arm A).
- To assess peposertib combined with cisplatin and curative-intent RT for squamous cell carcinoma of the head and neck (Arm B).
Main Methods:
- Phase 1 clinical trial (NCT02516813) involving ascending dose cohorts of peposertib.
- Patients received daily oral peposertib (tablet/capsule) with palliative RT (Arm A) or with intensity-modulated curative-intent RT and cisplatin (Arm B).
Main Results:
- Arm A (n=34): Most frequent adverse events included radiation skin injury, fatigue, and nausea. The RP2D was determined as 200 mg peposertib daily with RT.
- Arm B (n=11): Stomatitis, nausea, radiation skin injury, and dysgeusia were most common. A 50 mg peposertib dose was tolerable with RT and cisplatin.
- Arm B enrollment was discontinued due to insufficient drug exposure at the 50 mg dose, and an RP2D was not formally declared.
Conclusions:
- Peposertib, when administered orally up to 200 mg daily with palliative RT fractions, was well-tolerated.
- Combining peposertib with RT and cisplatin at a tolerable dose resulted in insufficient drug exposure, preventing formal RP2D declaration for this combination.
