Phase I Dose-Escalation Study of Pilaralisib (SAR245408, XL147) in Combination with Paclitaxel and Carboplatin in Patients with Solid Tumors

Jennifer Wheler, David Mutch, Joanne Lager, Christelle Castell, Li Liu, Jason Jiang, Anne M Traynor, Jennifer Wheler, David Mutch, Joanne Lager, Christelle Castell, Li Liu, Jason Jiang, Anne M Traynor

Abstract

Lessons learned: Despite involvement of PI3K pathway activation in tumorigenesis of solid tumors, single-agent PI3K inhibitors have shown modest clinical activity.Preclinical evidence suggests that combining PI3K pathway inhibitors and chemotherapy can enhance antitumor effects.In patients with solid tumors, the PI3K inhibitor pilaralisib had a favorable safety profile but did not enhance the antitumor activity of paclitaxel plus carboplatin.Further clinical evaluation is warranted to identify effective combination strategies with PI3K pathway inhibitors.

Background: Pilaralisib (SAR245408) is an oral, pan-class I phosphoinositide 3-kinase (PI3K) inhibitor. This phase I dose-escalation study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics of pilaralisib in capsule and tablet formulations, administered in combination with paclitaxel and carboplatin in patients with advanced solid tumors.

Methods: A 3 + 3 design was used. Pilaralisib was administered once daily (QD); paclitaxel (up to 175 mg/m2) and carboplatin (up to area under the curve [AUC] of 6) were administered on day 1 of 21-day cycles. An MTD expansion cohort of patients with endometrial carcinoma was included.

Results: Fifty-eight patients were enrolled. Six patients (10.3%) had dose-limiting toxicities, of which only rash (two patients, 3.4%) occurred in more than one patient. The MTD of pilaralisib tablets in combination with paclitaxel and carboplatin was determined to be 200 mg QD. The most frequently reported adverse events (AEs) of any grade were neutropenia (67.2%) and thrombocytopenia (67.2%). PK data showed no interaction between pilaralisib and paclitaxel/carboplatin. Tumor tissue showed moderate inhibition of PI3K and mitogen-activated protein kinase (MAPK) pathways. Seven of 52 evaluable patients had a partial response (PR; 13.5%).

Conclusion: Pilaralisib had a favorable safety profile but did not enhance the antitumor activity of paclitaxel plus carboplatin in solid tumors. The Oncologist 2017;22:377-378.

Trial registration: ClinicalTrials.gov NCT00756847.

© AlphaMed Press; the data published online to support this summary is the property of the authors.

Figures

Figure 1.
Figure 1.
PI3K and MAPK pathway inhibition in paired tumor biopsies. Cryopreserved tumor biopsy samples were serially sectioned at 10 microns; representative fields were captured at ×400 magnification. (A): A patient with colon adenocarcinoma (liver metastasis biopsies) receiving 200 mg pilaralisib/150 mg/m2 paclitaxel/AUC 5 carboplatin. Tumor molecular alterations were detected in KRAS, PIK3CA, and TP53 genes. (B): A patient with cervical adenocarcinoma receiving 200 mg pilaralisib/175 mg/m2 paclitaxel/AUC 6 carboplatin. Tumor molecular alteration was detected in PIK3CA gene (I391M polymorphism). Abbreviations: AUC, area under the curve; EBP1, EIF4E‐binding protein‐1; ERK, extracellular signal‐regulated kinase; MAPK, mitogen‐activated protein kinase; PI3K, phosphoinositide 3‐kinase.
Figure 2.
Figure 2.
Mean plasma concentration of pilaralisib over time on cycle 1, day 1 (A) and cycle 2, day 1 (B). Abbreviations: AUC, area under the curve; SD, standard deviation.
Figure 3.
Figure 3.
Maximum change in target lesions in patients treated with the combination of pilaralisib, paclitaxel, and carboplatin. Bar colors indicate prior treatment with paclitaxel and/or carboplatin. Abbreviations: CR, complete response; PR, partial response.
Figure 4.
Figure 4.
Mutational analysis of tumor tissue and circulating tumor DNA. (A): Dose‐escalation cohort: molecular profiling for gene alterations was performed on archival tumor tissue samples using Sanger sequencing (n = 21), and PTEN protein expression status was evaluated using IHC (n = 12). (B): Endometrial cohort (n = 17). KRAS, PIK3CA, BRAF mutational status at start of pilaralisib treatment (cycle 1, day 1) was assessed in cell‐free circulating tumor DNA obtained from peripheral blood samples using BEAMing assays (Sysmex Inostics). Key: yellow, no alteration detected; blue, gene alteration or altered protein expression (H score <50); grey, status unknown. Abbreviations: EGFR, epidermal growth factor receptor; IHC, immunohistochemistry; PTEN, phosphatase and tensin homolog.

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Source: PubMed

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