A phase I study to evaluate the safety, pharmacokinetics, and pharmacodynamics of PF-06939999 (PRMT5 inhibitor) in patients with selected advanced or metastatic tumors with high incidence of splicing factor gene mutations

Abstract

Background: Protein arginine methyltransferase 5 (PRMT5) methylates multiple substrates dysregulated in cancer, including spliceosome machinery components. PF-06939999 is a selective small-molecule PRMT5 inhibitor.

Patients and methods: This phase I dose-escalation and -expansion trial (NCT03854227) enrolled patients with selected solid tumors. PF-06939999 was administered orally once or twice a day (q.d./b.i.d.) in 28-day cycles. The objectives were to evaluate PF-06939999 safety and tolerability to identify maximum tolerated dose (MTD) and recommended part 2 dose (RP2D), and assess pharmacokinetics (PK), pharmacodynamics [changes in plasma symmetric dimethylarginine (SDMA) levels], and antitumor activities.

Results: In part 1 dose escalation, 28 patients received PF-06939999 (0.5 mg q.d. to 6 mg b.i.d.). Four of 24 (17%) patients reported dose-limiting toxicities: thrombocytopenia (n = 2, 6 mg b.i.d.), anemia (n = 1, 8 mg q.d.), and neutropenia (n = 1, 6 mg q.d.). PF-06939999 exposure increased with dose. Steady-state PK was achieved by day 15. Plasma SDMA was reduced at steady state (58%-88%). Modulation of plasma SDMA was dose dependent. No MTD was determined. In part 2 dose expansion, 26 patients received PF-06939999 6 mg q.d. (RP2D). Overall (part 1 + part 2), the most common grade ≥3 treatment-related adverse events included anemia (28%), thrombocytopenia/platelet count decreased (22%), fatigue (6%), and neutropenia (4%). Three patients (6.8%) had confirmed partial response (head and neck squamous cell carcinoma, n = 1; non-small-cell lung cancer, n = 2), and 19 (43.2%) had stable disease. No predictive biomarkers were identified.

Conclusions: PF-06939999 demonstrated a tolerable safety profile and objective clinical responses in a subset of patients, suggesting that PRMT5 is an interesting cancer target with clinical validation. However, no predictive biomarker was identified. The role of PRMT5 in cancer biology is complex and requires further preclinical, mechanistic investigation to identify predictive biomarkers for patient selection.

Keywords: PF-06939999; PRMT5 inhibitor; dose escalation; dose expansion; phase I; solid tumors.

Figure 1

PK and PD of PF-06939999. (A) Concentration–time profiles of PF-06939999 on day 1 and day 15 (geometric mean + SD, linear scale; PK concentration analysis set).^a (B) Plasma SDMA levels over time after the first dose of PF-06939999.^{b a}Summary statistics were calculated by setting concentration values below the LLOQ (0.250 ng/ml) to zero. Error bars are not presented when n < 3. ^bPF-06939999 activity on the PD biomarker SDMA was assessed by a plasma-based LC/MS assay. For Part 1, samples for SDMA analysis were collected at pre-dose and 2 and 6 h post-dose C1D1; 12 h post-dose C1D1 or pre-dose C1D2; pre-dose C1D8; pre-dose and 2 and 6 h post-dose C1D15; and pre-dose C1D22, C2D1, and C3D1. For Part 2, samples were collected at pre-dose C1D1, C1D8, C1D15, C1D22, C2D1, C3D1, and EOT. BID, twice daily;C, Cycle; D, Day; EOT, end of treatment; LLOQ, lower limit of quantification; PD, pharmacodynamics; PK, pharmacokinetics; QD, once daily; SDMA, symmetric dimethylarginine; Std, standard deviation.

Figure 2

Tumor response in the response-evaluable analysis set and duration of treatment in the safety analysis set. (A, B) Best percentage change from baseline in sum of diameters for target lesions.^a (C, D) Duration of treatment.^{b a}Only included patients of the response-assessable population, defined as all patients who received at least one dose of PF-06939999 and had baseline disease assessment or measurable disease at baseline, and at least one post-baseline disease assessment. The response-assessable population included 44 patients with assessments of target lesions at baseline and at least one nonmissing post-baseline percentage change from baseline assessment up to the time of progressive disease or new anticancer therapy. Of the 44 patients, 2 patients in part 2A (2L+ NSCLC 6 mg q.d. PF-06939999 treatment group) did not have all target lesions assessed at post-baseline, and the post-baseline percentage change in tumor size from baseline did not meet the ≥20% criteria; therefore, they were considered as not assessable and excluded in the waterfall plots. Tumor response was based on investigator assessment using RECIST v1.1. ^bDuration was from the first to the last day (inclusive) of each study treatment. PR, SD, and progressive disease were based on investigator assessment. The number included in each label of the y-axis of panels C and D is patient ID. 2L+ NSCLC, patients with NSCLC who had progressed after at least one line of checkpoint inhibitors and one line of platinum-based chemotherapy; BC, bladder cancer; b.i.d., twice daily; CC, cervical carcinoma; ECM, metastatic endometrial cancer; ENDC, endometrial cancer; HNSCC, head and neck squamous cell carcinoma; LA, lung adenocarcinoma; LC/MS, liquid chromatography–mass spectrometry; MSCC, metastatic squamous cell carcinoma; NE, not evaluable; NSCLC, non-small-cell lung cancer; EC, esophageal carcinoma; PR, partial response; q.d., once daily; SCCL, squamous cell carcinoma of the lung; SD, stable disease; UC, urothelial carcinoma.

Figure 2

Tumor response in the response-evaluable analysis set and duration of treatment in the safety analysis set. (A, B) Best percentage change from baseline in sum of diameters for target lesions.^a (C, D) Duration of treatment.^{b a}Only included patients of the response-assessable population, defined as all patients who received at least one dose of PF-06939999 and had baseline disease assessment or measurable disease at baseline, and at least one post-baseline disease assessment. The response-assessable population included 44 patients with assessments of target lesions at baseline and at least one nonmissing post-baseline percentage change from baseline assessment up to the time of progressive disease or new anticancer therapy. Of the 44 patients, 2 patients in part 2A (2L+ NSCLC 6 mg q.d. PF-06939999 treatment group) did not have all target lesions assessed at post-baseline, and the post-baseline percentage change in tumor size from baseline did not meet the ≥20% criteria; therefore, they were considered as not assessable and excluded in the waterfall plots. Tumor response was based on investigator assessment using RECIST v1.1. ^bDuration was from the first to the last day (inclusive) of each study treatment. PR, SD, and progressive disease were based on investigator assessment. The number included in each label of the y-axis of panels C and D is patient ID. 2L+ NSCLC, patients with NSCLC who had progressed after at least one line of checkpoint inhibitors and one line of platinum-based chemotherapy; BC, bladder cancer; b.i.d., twice daily; CC, cervical carcinoma; ECM, metastatic endometrial cancer; ENDC, endometrial cancer; HNSCC, head and neck squamous cell carcinoma; LA, lung adenocarcinoma; LC/MS, liquid chromatography–mass spectrometry; MSCC, metastatic squamous cell carcinoma; NE, not evaluable; NSCLC, non-small-cell lung cancer; EC, esophageal carcinoma; PR, partial response; q.d., once daily; SCCL, squamous cell carcinoma of the lung; SD, stable disease; UC, urothelial carcinoma.