Phase I study of taselisib in Japanese patients with advanced solid tumors or hormone receptor-positive advanced breast cancer

2.1 Study design

This was a phase I, multicenter, open-label, modified 3 + 3 dose escalation study (JapicCTI-142630). This study was conducted in 2 stages: stage 1 evaluated the use of single and repeated doses of taselisib in Japanese patients with solid tumors, and stage 2 evaluated the use of taselisib with fulvestrant (Faslodex^®) in Japanese patients with HR-positive locally advanced or recurrent breast cancer. Maximal doses of taselisib in stage 1 and stage 2 were planned as possible doses for use in future studies.

The study protocol was approved by Institutional Review Boards prior to patient recruitment and conducted in accordance with International Conference on Harmonization E6 Guidelines for Good Clinical Practice and the Declaration of Helsinki. All patients provided written informed consent.

2.2 Patients

Japanese patients were included in the study if they were aged ≥20 years, had evaluable or measurable disease, a life expectancy of ≥12 weeks, an ECOG PS of 0 to 1, lesions that could be assessed by diagnostic imaging, adequate hematological and organ function and, for patients that were not treatment naïve, 2-4 weeks washout from previous cancer therapy prior to the start of taselisib dosing. For stage 1 of the study, patients were included if they had histologically or cytologically documented advanced or recurrent solid cancers, for which standard treatment is ineffective or for which there is no established standard treatment. For stage 2, patients were included only if they were postmenopausal women who were diagnosed with inoperable advanced or recurrent breast cancer. Patients had to have HR-positive disease by IHC and be HER2-negative on IHC and/or ISH of breast cancer tissue from primary tumors or from advanced or recurrent breast cancers. Patients were also required to have previously received endocrine therapy or were approved for initiating endocrine therapy.

Patients were excluded from any stage of the study if they had previous hypersensitivity to the excipients in taselisib tablets, diabetes mellitus requiring medication, central nervous system metastases, non-infectious bowel inflammation, or severe uncontrolled systemic cardiac, lung, or liver disease. Patients were also excluded from stage 2 of the study if they had received 2 or more previous chemotherapy regimens for advanced or recurrent breast cancer, had experienced previous hypersensitivity to components of fulvestrant, or had more than 1 primary cancer with a disease-free interval of less than 5 years. The PIK3CA mutation was detected by using an archived sample from the primary or recurrent tumor at the local site.

2.3 Study treatments

Study design and taselisib dosage procedures are summarized in Figures 1 and 2. In stage 1 of the study, taselisib monotherapy was given to successive cohorts of patients at escalating doses of 2, 4, and 6 mg/d (cohorts 1, 2, and 3, respectively) (Figure 1). Film-coated 2-mg tablets were used. Oral doses of taselisib were given once daily under fasting conditions, for 28-day cycles.12 Prior to starting the first cycle of treatment, patients received a single dose of taselisib, and day 1 of the first cycle was started 4-7 days after the single dose (Figure 2).

In stage 2 of the study, successive cohorts of patients received taselisib 2 or 4 mg/d in combination with fulvestrant 500 mg (cohorts A and B, respectively) (Figure 1). Similar to stage 1 of the study, taselisib was given orally once daily under fasting conditions and 1 cycle of treatment was 28 days. In stage 2, fulvestrant was injected i.m. before the taselisib dose on day 1 and day 15 of cycle 1, and day 1 of cycle 2 or later (Figure 2).

In both stages of the study, patients continued treatments until intolerable toxicity, PD, or withdrawal of consent.

2.4 Outcomes

Primary objectives of the present study were to evaluate the safety (including determining any DLT) and pharmacokinetics of taselisib.

DLT were set as determination factors to decide whether or not to proceed to the next cohort, and were defined as taselisib-related AE observed during the DLT evaluation period in each stage. The DLT evaluation period in stage 1 was from day 1 of cycle 0 to day 28 of cycle 1 (32-35 days) and the DLT evaluation period in stage 2 was from day 1 to day 28 of cycle 1 (Figure 2). The following were considered DLT: fasting grade 4 hyperglycemia, fasting grade 3 hyperglycemia persisting for ≥1 week after the start of treatment with oral diabetes medication, grade 4 fasting hypercholesterolemia or hypertriglyceridemia persisting for ≥2 weeks after the start of treatment with hyperlipidemia medication, grade ≥3 increased total bilirubin or alanine aminotransferase or aspartate aminotransferase, alkaline phosphatase, or any grade ≥3 non-hematological toxicity, with the exception of grade 3 diarrhea, nausea, vomiting, or skin toxicity. Hematological toxicities defined as a DLT included grade 4 thrombocytopenia or grade 4 neutropenia with fever lasting >5 days or accompanied by ≥38.0°C fever. The need to interrupt drug treatment for a total of 14 days or more during the DLT evaluation period because of AE was also considered a DLT.

Safety outcomes included the incidence, nature, and severity of AE (including DLT, laboratory test values, vital signs, and any other changes in patient condition considered clinically important). AE were graded according to the NCI Common Terminology Criteria for Adverse Events v4.0.

Plasma drug concentration-time data were used to calculate the following pharmacokinetic parameters of taselisib for both the single dose and repeated doses: C_max, terminal t_1/2, and AUC. AUC_last was defined as the area from time 0 to time of last measurable concentration. During stage 1, plasma samples were collected during cycle 0 at predose, 0.5, 1, 2, 3, 4, 8, 24, 48, and 72 hours after dose, during cycle 1 at predose on day 1, at predose, 0.5, 1, 2, 3, 4, 8, and 24 hours after dose on day 8, at predose, 0.5, 1, 2, 3, 4, 8, and 24 hours after dose on day 15, and at predose on day 22, during cycle 2 or later cycles at predose on day 1, and on the last day of the study (Figure 2). During stage 2, plasma samples were collected during cycle 1 at predose, 0.5, 1, 2, 3, 4, 8, and 24 hours after dose on day 1, at predose, 0.5, 1, 2, 3, 4, 8, and 24 hours after dose on day 15, during cycle 2 and cycle 6 at predose on day 1, and on the last day of the study (Figure 2). Concentration of taselisib was determined using a validated liquid chromatography-tandem mass spectrometry analytical procedure, with a lower limit of quantification of 0.05 ng/mL.

The secondary objective of the study was to determine the preliminary efficacy of taselisib in both stages of the study. Efficacy was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.13 Assessment of lesions in stage 1 was conducted before the start of the study.

2.5 Statistical analysis

In both stages of the study, all statistical analyses were descriptive in nature; thus, no formal hypothesis testing was conducted. Efficacy was analyzed in the full analysis set, which comprised all patients who received at least 1 dose of study treatment. Safety was analyzed in the safety population, which comprised all patients who received at least 1 dose of treatment. All statistical analyses were carried out using SAS, version 9.2 (SAS Institute, Cary, NC, USA).

3.1 Participants

This study was conducted between 21 August 2014 and 17 May 2017. Overall, 9 patients were included in stage 1 and 6 patients were included in stage 2. Baseline characteristics of patients included in both stages of the study are reported in Table 1. In stage 1, all patients had a baseline ECOG PS of 0. PIK3CA mutations were found in 3 patients, including 1 PIK3CA E542K mutation and 2 PIK3CA H1047R mutations. In stage 2, 2 patients had baseline ECOG PS 1. PIK3CA mutations were found in 2 patients.

3.2 Safety

Taselisib was well tolerated up to 6 mg as monotherapy in stage 1 and up to 4 mg as combination therapy in stage 2. No DLT were experienced in any cohort of patients and there were no deaths in the study of any cause. At least 1 treatment-related AE was experienced by all patients (100%) in stage 1 and in 83.3% of patients in stage 2 (Table 2). In stage 1, a total of 36 treatment-related AE occurred in 9 patients. Common treatment-related AE that occurred in 2 or more patients were rash (5 patients), diarrhea (4 patients), stomatitis (4 patients), decreased appetite (2 patients), and headache (2 patients). Of these treatment-related AE, grade ≥3 treatment-related AE were rash and diarrhea (1 patient each). A total of 5 serious AE (SAE) occurred in 3 patients: vertigo in 1 patient in cohort 2 which occurred 2 weeks after the last dose of taselisib and improved with supportive care, and erythema multiforme, rash, diarrhea, and lung infection in 2 patients in cohort 3. The patients discontinued taselisib as a result of these SAE in which the rash, diarrhea, and lung infection in cohort 3 were treatment-related. All patients with SAE recovered after discontinuation of treatment. In stage 2, a total of 32 treatment-related AE occurred in 5 patients. Common treatment-related AE that occurred in 2 or more patients were diarrhea (4 patients), stomatitis (4 patients), rash (4 patients), colitis (2 patients), and dry skin (2 patients). Of these treatment-related AE, grade ≥3 treatment-related AE were diarrhea and rash (1 patient each) and colitis (2 patients). Four SAE occurred in 3 patients in stage 2; they were 1 event of decreased appetite leading to discontinuation of treatment in 1 patient in cohort A, and 2 events of colitis and 1 event of gingivitis in 2 patients in cohort B. The patients discontinued treatment as a result of the colitis and recovered with corticosteroid. All of these SAE were considered treatment-related.

3.3 Pharmacokinetics

In stage 1, single and multiple oral doses of taselisib were rapidly absorbed with a t_max ranging from 0.483 to 8.00 hours (Table 3). Plasma concentration of taselisib gradually declined, with a t_1/2 of 12.9-32.0 hours. Linearity was observed after both single and multiple doses of taselisib and no accumulation was found for multiple doses beyond the level estimated by the single dose (Figure 3). In stage 2, after single and multiple oral doses of taselisib plus fulvestrant 500 mg, taselisib was rapidly absorbed with a t_max ranging from 0.933 to 4.07 hours; similar to the pharmacokinetics observed in stage 1 of the study, the plasma concentration of taselisib then gradually declined, with a t_1/2 of 16.1-26.5 hours (Table 3; Figure 3).

3.4 Efficacy

In stage 1, all 9 patients had target lesions and were eligible for assessment per RECIST 1.1 after starting taselisib treatment. Three patients continued the study treatment for ≥6 months (Figure 4A). The longest treatment duration was 13.3 months. PR was seen in 2 patients, SD was seen in 5 patients, and PD was seen in 2 patients, giving an overall response rate of 22% (2/9) and a disease control rate of 78% (7/9; Figure 5). The 2 patients with PR both had tumors with PIK3CA mutations (Figure 5), and the duration of response for the 2 patients with PR was 127 and 169 days, respectively. PFS was 38-398 days in stage 1. In stage 2, 4 patients had target lesions and were assessed after starting taselisib treatment. Two patients continued the study treatment for ≥12 months (Figure 4B). The longest treatment duration was 29.5 months. PR was observed in 1 patient and SD in 5 patients, giving an overall response rate of 17% (1/6) and a disease control rate of 100% (6/6; Figure 5). The 1 patient who achieved PR was positive for PIK3CA mutation (Figure 5), and the duration of response in this patient was 613 days. PFS was 110-884 days in stage 2.