Between 22 March 2018 and 29 March 2019, 25 patients were enrolled from six centers in the USA, France, Spain, the UK, and South Korea. Of these, four patients failed screening prior to receiving study drug, two did not receive study drug for other reasons, and 19 patients were treated with the study drug (all treated population). Baseline characteristics of the patients who received TAS0728 treatment per the protocol for 21-day cycles are summarized in Table 1. Seven patients received study drug at the highest dose administered in this study (200 mg BID) before a dose reduction to 150 mg BID was conducted in 6 patients. For the overall all treated population, the median treatment duration was 81.0 days (range 1–489 days) and the median number of cycles was 4.6 (Fig.1). The mean relative dose intensity (actual amount of dose administered/amount of planned dose, %) was 74.9% (range 5%–100%). Across the 19 patients who received ≥1 dose of TAS0728, the mean age was 57.7 years (range 29–79) and all had an ECOG performance status of 0 or 1. Breast cancer and non-small-cell lung cancer (NSCLC) (n=3 patients each) were the most common sites of primary tumors among the patients in the study. The mean time since initial cancer diagnoses was 31.5 months. All 19 treated patients had received ≥2 prior lines of systemic therapy. HER2 amplification was detected in 7 (36.8%) of the 19 treated patients, and 6 of the patients (31.6%) had HER2 overexpression at baseline. Three (15.7%) and four (21.0%) patients had HER2 or HER3 mutations, respectively (Table 1). One patient in the 150 mg BID cohort had HER2 amplification and a HER2 mutation (G776V).
Of the 19 patients treated with TAS0728, 18 (94.7%) discontinued treatment, most (n=14, 73.7%) due to disease progression. Reasons for treatment discontinuation in the other patients were fatal cardiac arrest (1 patient; 5.3%), AEs (1 patient; 5.3%); and patient decision to withdraw from treatment (n=2; 10.5%). At the time of data cut-off for the final analysis (9 September 2019), one patient was still receiving TAS0728 (Fig.1); this patient had received TAS0728 50 mg BID for 489 days at that date and at the time of writing (October 2020) was continuing to receive TAS0728 treatment.
The study was stopped due to unacceptable toxicity during the dose-escalation, therefore the MTD was not determined. Overall, the incidence of AEs reported during the study was higher at doses of 150 mg and 200 mg BID TAS0728 compared with lower doses (Table 2); however, all 19 (100.0%) patients in the all treated population experienced an AE during the study at all doses administered, most of which were considered by the investigator to be treatment-related (Table 3).
The TRAEs with the highest incidence (≥20% of patients) were diarrhea (78.9%), nausea (21.1%), vomiting (21.1%), and fatigue (21.1%). Almost one third (31.6%) of the TRAEs experienced overall were considered ≥Grade 3 in severity, with diarrhea having the highest incidence (26.3%). Other ≥Grade 3 TRAEs were acute kidney injury, proteinuria, and cardiac arrest (1 patient, 5.3% each). When broken down by dose level, the highest incidence of AEs experienced at each dose level cohort was diarrhea. At the 50-mg dose level cohort, 2 of 3 (66.7%) patients had diarrhea, 1 at a severity ≥Grade 3. Hyperuricemia was also experienced in 2 of 3 (66.7%) patients at this dose. At the 100-mg dose level cohort, all 3 (100%) patients experienced diarrhea, all at a severity of Grade 1 or Grade 2. At the 200-mg dose, 6 of 7 (85.7%) patients experienced diarrhea, 3 at a severity ≥Grade 3. Other AEs experienced at this dose in ≥2 patients were anemia (5/7 patients, 71.4%), cough, dermatitis acneiform, fatigue, and pyrexia (3/7 patients each, 42.9%), and nausea, vomiting, asthenia, edema peripheral, dry skin, urinary tract infection, decreased appetite, and hypokalemia (2/7 patients each, 28.6%). At the reduced dose of 150 mg BID, 4 of 6 (66.7%) patients experienced diarrhea, 2 at a severity ≥Grade 3. Other AEs experienced at this dose in ≥2 patients were vomiting, pyrexia, and back pain.
Two patients at the 200-mg BID dose level experienced a DLT of diarrhea ≥Grade 3 that lasted >48 hours and was unresponsive to intensive antidiarrheal medication (Table 4). Subsequently, the dose of TAS0728 was reduced to 150 mg BID. At this dose, 1 patient experienced a DLT of diarrhea ≥Grade 3 that lasted >48 hours and was unresponsive to intensive antidiarrheal medication.
A total of 4 patients died during the study; 3 of 4 deaths occurred >30 days after the last dose of study treatment, all due to clinical progression. The other patient had an SAE with an outcome of death: this patient had a cardiac arrest after completing 1 cycle (21 days) of TAS0728 at a dose of 150 mg BID. This patient was a 42-year-old male patient with colorectal cancer and metastases to the liver and lungs, with no known history of heart disease. No abnormal results had been observed in his screening or in-study ECG assessments. The cardiac arrest occurred during the patient’s second cycle of TAS0728. After onset of dizziness and loss of consciousness, the patient underwent defibrillation by emergency services before being taken to hospital. Thereafter, the patient was unresponsive, intubated, and started on amiodarone drip for arrhythmia. Diagnostic workup was negative for coronary ischemia (troponin I was not elevated). Blood cultures were negative, and no acute cardiopulmonary abnormality was seen on chest x-ray. CT of the head showed loss of normal gray-white matter differentiation with decreased sulcation over the cerebral hemispheres bilaterally suggesting global anoxic brain ischemia. The patient died the following morning. The investigator and sponsor considered the event of cardiac arrest possibly related to TAS0728.
In the overall population, 8 (42.1%) of 19 patients experienced ≥1 SAE. Of these, five (26.3%) patients experienced an SAE that was Grade 3 or higher in severity. Serious AEs were experienced at dose level cohorts of 50 mg BID, 200 mg BID, and 150 mg BID, and included pyrexia (4 patients, 21.1%), diarrhea (2 patients, 10.5%), and dysphagia, cellulitis, clostridium colitis, cardiac arrest, back pain, and acute kidney injury (1 patient each, 5.3%). The SAE with the overall highest incidence was pyrexia, which occurred in 4 patients (2 each at doses of 200 mg and 150 mg BID). Three (15.8%) of the 19 patients in the all treated population experienced an SAE considered related to study drug, including SAEs of diarrhea (200- and 150-mg BID) and cardiac arrest (150 mg BID).
In total, 4 patients experienced an AE that led to study drug discontinuation. At the dose level of TAS0728 100 mg BID one patient experienced blood albumin decreased (Grade 2), one patient experienced myalgia (Grade 1) and abdominal pain (Grade 1). At the dose level of TAS0728 150 mg BID, one patient experienced cardiac arrest, (Grade 5/fatal). At the dose level of TAS0728 200 mg BID, one patient experienced acute kidney injury (Grade 3) and weight decreased (Grade 2).
No clinically meaningful changes from baseline were noted during the study for clinical laboratory results or for standard 12-lead ECG parameters. All patients had an ECOG performance status score of 0 or 1 at baseline. In all patients having an ECOG score of 0 at baseline, this score worsened to 1 during the study. Most of the patients with an ECOG score of 1 at baseline did not have a change in status during the study; however, 2 patients (1 in each of the 200-mg and 150-mg BID cohorts) worsened to an ECOG status of 2 during the study.
PK parameters of TAS0728 on cycle 1, day 1 and cycle 2, day 1 are summarized in Table 5, respectively. Absorbed TAS0728 reached Cmax at approximately 0.5 to 4 hours after oral administration, and then declined with t1/2 of approximately 2.0 hours on cycle 1, day 1. Covariability values of Cmax and AUCs on cycle 1, day 1 were from 16.2% to 97.8%. Due to the dose interruption/reduction or discontinuation, the number of patients who represented accurately the steady-state PK on cycle 2, day 1 was limited. Tmax and t1/2 values observed at the start of cycle 2 were similar to those on Cycle 1, Day 1. No significant accumulation of TAS0728 exposure was observed following the BID multiple-dose administration.
Out of a total of 19 treated patients, a total of two objective responses were observed: a partial response (PR) in a patient with NSCLC and HER2 mutation (G788_P780dup) treated at 50 mg BID and a PR in a patient with biliary tract cancer (BTC) with HER2 amplification confirmed by FISH treated at 200 mg BID. In all, disease control (best overall tumor response of PR or stable disease [SD]) was observed in 10 patients (Fig.2). Note that 1 patient in the 50-mg BID group had only non-target lesions (therefore there was no change in target lesion from baseline), this patient was included in the 14 patients with tumor response data (as a best response of SD), but not included in Fig.2.