Kristen J. Pierce

Safety, Pharmacokinetic, and Pharmacodynamic Phase I Dose-Escalation Trial of PF-00562271, an Inhibitor of Focal Adhesion Kinase, in Advanced Solid Tumors

PURPOSE PF-00562271 is a novel inhibitor of focal adhesion kinase (FAK). The objectives of this study were to identify the recommended phase II dose (RP2D) and assess safety and tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of PF-00562271. PATIENTS AND METHODS Part 1 was a dose escalation without and with food. Part 2 enrolled specific tumor types in an expansion at the RP2D and also assessed the effect of PF-00562271 on single-dose midazolam PK in a subgroup of patients. RESULTS Ninety-nine patients (median age, 60 years; 98% with Eastern Cooperative Oncology Group performance status of 0 or 1) were treated in 12 fasting and three fed cohorts. The 125-mg twice-per-day fed dose was deemed the maximum-tolerated dose (MTD) and RP2D. Grade 3 dose-limiting toxicities included headache, nausea/vomiting, dehydration, and edema. Nausea was the most frequently observed toxicity (60% of patients, all grades 1 or 2 at RP2D). PF-00562271 exposure increased with increasing dose; serum concentration-time profiles showed characteristic nonlinear disposition. Steady-state exposures were reached within 1 week. On coadministration, geometric mean values of midazolam maximal observed serum concentration and area under the serum concentration-time curve increased by 60% and more than two-fold, respectively. Of 14 patients evaluable by [(18)F]fluorodeoxyglucose positron emission tomography in the expansion cohorts, seven metabolic responses were observed. With conventional imaging, 31 patients had stable disease at first restaging scans, and 15 of these remained stable for six or more cycles. CONCLUSION The MTD and RP2D of PF-00562271 is 125 mg twice per day with food. PF-00562271 displayed time- and dose-dependent nonlinear PK and is likely a potent CYP 3A inhibitor. This first-in-class study supports further investigation of FAK as a promising therapeutic target.

Phase I Study of the Safety, Tolerability, and Pharmacokinetics of Oral CP-868,596, a Highly Specific Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor in Patients With Advanced Cancers

PURPOSE This phase I, first-in-human study evaluated the safety, tolerability, pharmacokinetics, and maximum-tolerated dose (MTD) of an oral platelet-derived growth factor receptor inhibitor, CP-868,596. PATIENTS AND METHODS Patients with advanced solid tumors were eligible. Dose escalations were performed in three groups with two formulations: uncoated on an empty stomach (UES), uncoated with food (UFED), and film-coated (FC) without food. Initial dose escalation in the UES group was followed by parallel escalations in the UFED and FC groups. RESULTS Fifty-nine patients enrolled. CP-868,596 was escalated from 100 mg to 340 mg daily in the UES group, from 60 mg to 100 mg twice daily in the UFED group, and from 100 mg once daily to 140 mg twice daily in the FC group. MTDs were 200 mg daily in the UES group and 100 mg twice daily in the FC group; MTD was not reached at 100 mg twice daily in the UFED group. Dose-limiting toxicities included hematuria, increased gamma-glutamyltransferase or ALT, insomnia, and nausea/vomiting. Most treatment-related AEs were of grades 1 to 2 severity; nausea, vomiting, and diarrhea were reported most frequently. Administration with food generally improved tolerability. CP-868,596 was absorbed slowly; systemic exposure parameters appeared to increase greater than proportionally with dose. Mean serum concentrations exceeded the preclinically predicted minimal efficacious concentration (ie, 16 ng/mL) at all dosages. Food and film coating apparently increased interpatient variability of the maximum observed plasma concentration and the area under the concentration-time curve. No objective responses were reported, and eight patients achieved stable disease (mean duration, 5.7 months). CONCLUSION CP-868,596 potentially demonstrated greater than dose-proportional pharmacokinetics. The recommended dosage of 100 mg twice daily with food was well tolerated. Additional development as a single agent in selected populations or in combination with chemotherapy in broader populations is warranted.

First-In-Human Study of PF-05212384 (PKI-587), a Small-Molecule, Intravenous, Dual Inhibitor of PI3K and mTOR In Patients With Advanced Cancer

Purpose: To evaluate safety (primary endpoint), tolerability, pharmacokinetics, pharmacodynamic profile, and preliminary activity of the intravenous, pan-class I isoform PI3K/mTOR inhibitor PF-05212384 in patients with advanced solid tumors. Experimental Design: Part 1 of this open-label phase I study was designed to estimate the maximum-tolerated dose (MTD) in patients with nonselected solid tumors, using a modified continual reassessment method to guide dose escalation. Objectives of part 2 were MTD confirmation and assessment of preliminary activity in patients with selected tumor types and PI3K pathway dysregulation. Results: Seventy-seven of the 78 enrolled patients received treatment. The MTD for PF-05212384, administered intravenously once weekly, was estimated to be 154 mg. The most common treatment-related adverse events (AE) were mucosal inflammation/stomatitis (58.4%), nausea (42.9%), hyperglycemia (26%), decreased appetite (24.7%), fatigue (24.7%), and vomiting (24.7%). The majority of patients treated at the MTD experienced only grade 1 treatment-related AEs. Grade 3 treatment-related AEs occurred in 23.8% of patients at the MTD. No treatment-related grade 4–5 AEs were reported at any dose level. Antitumor activity was noted in this heavily pretreated patient population, with two partial responses (PR) and an unconfirmed PR. Eight patients had long-lasting stable disease (>6 months). Pharmacokinetic analyses showed a biphasic concentration–time profile for PF-05212384 (half-life, 30–37 hours after multiple dosing). PF-05212384 inhibited downstream effectors of the PI3K pathway in paired tumor biopsies. Conclusions: These findings demonstrate the manageable safety profile and antitumor activity of the PI3K/mTOR inhibitor PF-05212384, supporting further clinical development for patients with advanced solid malignancies. Clin Cancer Res; 21(8); 1888–95. ©2015 AACR.

Phase I, open-label, multicentre, dose-escalation, pharmacokinetic and pharmacodynamic trial of the oral aurora kinase inhibitor PF-03814735 in advanced solid tumours

This phase I study (ClinicalTrials.gov ID: NCT00424632) evaluated the safe dose, pharmacokinetics, and pharmacodynamics of the aurora kinase A and B inhibitor, PF-03814735. Patients with advanced solid tumours received oral, once-daily (QD) PF-03814735 on Schedule A: days 1-5 (5-100mg); or Schedule B: days 1-10 (40-60mg) of 21-day cycles. Fifty-seven patients were treated: 32 and 25 on Schedules A and B, respectively. Dose-limiting toxicities were: febrile neutropenia (Schedule A); and increased levels of aspartate amino transferase, left ventricular dysfunction, and prolonged low-grade neutropenia (Schedule B). Maximum tolerated doses were 80mg QD (Schedule A) and 50mg QD (Schedule B). Common treatment-related adverse events were mainly mild to moderate and included diarrhoea, fatigue, nausea, and vomiting. Nineteen patients achieved stable disease, which was prolonged in four cases. PF-03814735 was rapidly absorbed and demonstrated linear pharmacokinetics up to 100mg QD; mean terminal half-life ranged from 14.4 to 23.6h. Aurora B activity, assessed by histone H3 phosphorylation in mitotic cells, decreased in tumour tissue from 10/12 patients evaluated (range: -70% to -3%). (18)F-fluorodeoxyglucose positron emission tomography demonstrated metabolic responses in only 1/21 patients. PF-03814735 was generally well tolerated with manageable toxicities, and a recommended phase II dose could be established for both schedules. Aurora B activity was inhibited in tumour tissue, but clinical or metabolic antitumour activity was limited.

A randomized phase II non-comparative study of PF-04691502 and gedatolisib (PF-05212384) in patients with recurrent endometrial cancer.

OBJECTIVE PF-04691502 and gedatolisib (PF-05212384) are potent, dual PI3K/mTOR inhibitors. This phase II study (B1271004) was conducted in patients with recurrent endometrial cancer following platinum-containing chemotherapy. The primary endpoint was to assess clinical benefit response (complete or partial response, or stable disease for ≥16weeks) following treatment with PF-04691502 or gedatolisib. METHODS The main study consisted of four independent arms based on a Simon two-stage design. Patients were assigned to putative PI3K-basal (PF-04691502 or gedatolisib) or PI3K-activated (PF-04691502 or gedatolisib) arms based on stathmin-low or stathmin-high tumor expression, respectively. Japanese patients were also enrolled in a separate lead-in cohort. RESULTS In stage 1 (main study), eighteen patients were randomized to PF-04691502 and 40 to gedatolisib. The two PF-04691502 arms were discontinued early due to unacceptable toxicity, including pneumonia and pneumonitis. The most common treatment-related adverse events associated with gedatolisib were nausea (53%), mucosal inflammation (50%), decreased appetite (40%), diarrhea (38%), fatigue (35%), and dysgeusia and vomiting (each 30%). Clinical benefit response rate was 53% (10/19) in the gedatolisib/stathmin-low arm and 26% (5/19) in the gedatolisib/stathmin-high arm. Safety profile and pharmacokinetic characteristics of both drugs in the Japanese lead-in cohort were comparable to the Western population. CONCLUSIONS Gedatolisib administered by weekly intravenous infusion demonstrated acceptable tolerability and moderate activity in patients with recurrent endometrial cancer. PF-04691502 daily oral dosing was not well tolerated. Clinical benefit response criteria for proceeding to stage 2 were only met in the gedatolisib/stathmin-low arm. Stathmin-high expression did not correlate with greater treatment efficacy. ClinicalTrials.gov registration ID: NCT01420081.

Abstract 2278: Next-generation sequencing (NGS) analysis from a phase II single-agent gedatolisib study in patients with endometrial cancer

Genetic alterations in the PI3K pathway are abundant in endometrial cancer. Hence it is hypothesized that PI3K/mTOR inhibitors will have utility for treatment of endometrial cancer. Gedatolisib, also known as PF-384, is a potent and selective dual PI3K-mTOR inhibitor with broad anti-tumor activity in preclinical studies. Gedatolisib delivered weekly intravenously was investigated in a Phase II single-agent study of advanced endometrial cancer. The cumulative clinical benefit rate from 38 response evaluable patients was 39.5%, comparable to historical rates with mTOR inhibitors. A retrospective NGS analysis of archival biopsies from patients in the study was conducted using the Foundation Medicine Inc (FMI) Foundation One Test to explore potential predictive biomarkers for clinical benefit. Of the 26 patient samples submitted for analysis, data was obtained from 19 samples of which 17 had evaluable response data. Of these 17 samples, 6 were from patients who exhibited progressive disease (PD), 6 were from patients with stable disease (SD) and 5 were from patients that showed a partial response (PR) to treatment. In general, the best responders had a low mutation load while the worst responders had a higher mutation load. Whether large mutation burden was due to mismatch-repair defects determined by MSI status of the tumors is currently under investigation. PTEN alterations were found in tumors from patients that exhibited PD and SD, but not PR. Multiple genetic alterations in ARID1A were observed in 3 of 6 tumors from patients with PD. While PIK3CA alterations were frequently present, 2 of 5 patients with PR and 1 with SD exhibited an activating PIK3CA mutation at H1047R. Among 175 genes that were observed to be mutated in the analysis of 17 independent tumor samples, the top ranking genes associated with a reduction in tumor size (% change from baseline by RECIST 1.0; Wilcoxon rank sum test) were MAP3K1 (p = 0.027) and CTNNB1 (p = 0.050). Activating mutations in β-catenin were observed in tumor from 3 of 5 patients with PR and were not present in tumor from patients with PD or SD. Tumor from a patient who exhibited an outlier clinical response (stayed on study after 2 years on treatment) had an activating mutation in Akt at E17K and also a novel mutation in mTOR at F2184L. Computational modeling analysis revealed that the mutation did not have a significant impact on kinase structure or ligand binding. KRAS mutations did not appear to correlate with clinical response. This study highlights both the wealth of information provided by NGS analysis, but also the complexity of NGS data analysis and interpretation. Citation Format: Nuzhat Pathan, Patricia English, Keith Ching, Stephen Huang, Mehran Jalaie, Kristen Pierce, Jennifer Vermette. Next-generation sequencing (NGS) analysis from a phase II single-agent gedatolisib study in patients with endometrial cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2278.

Continual Reassessment Method for a First-in-Human Trial: From Design to Trial Implementation

We present a case study of a Phase 1 oncology dose-escalation trial utilizing modified Continual Reassessment Method (CRM). Learning about the dose–toxicity relationship and choosing the correct Maximum Tolerated Dose (MTD) to take forward into Phase II is one of the most challenging research questions in Phase 1 oncology trials. CRM is a Bayesian adaptive design targeting a specific Dose Limiting Toxicity (DLT) rate, e.g., 25 %. Similar to the traditional 3 + 3 designs used in oncology Phase 1 trials, learning about drug’s toxicity profile with CRM occurs in real time. However, since CRM algorithm incorporates dose–toxicity modeling in the learning process, its ability to identify the correct Maximum Tolerated Dose is substantially improved, compared to the traditional 3 + 3 design. Such design also results in more patients being allocated to tolerable doses with therapeutic potential than would be the case in a more traditional 3 + 3 dose-escalation trial. This trial was designed and executed using a custom-developed and validated software package which helped to alleviate substantial increase in overhead cost typically associated with planning and implementation of such designs. We present the whole “story” of the trial from beginning to end, including selection of study design, assessment of its operating characteristics via simulations, execution, study results, and lessons learned.