6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety population described in WARNINGS and PRECAUTIONS reflects exposure to TRUQAP 400 mg orally, twice a day for 4 days followed by 3 days off, in combination with fulvestrant, in 355 patients in CAPItello-291 until disease progression or unacceptable toxicity.
Among the 355 patients who received TRUQAP, 52% were exposed for 6 months or longer, and 27% were exposed for greater than one year. In this safety population, the most common (≥ 20%) adverse reactions including laboratory abnormalities were diarrhea (72%), cutaneous adverse reactions (58%), increased random glucose (57%), decreased lymphocytes (47%), decreased hemoglobin (45%), increased fasting glucose (37%), nausea and fatigue (35% each), decreased leukocytes (32%), increased triglycerides (27%), decreased neutrophils (23%), increased creatinine (22%), vomiting (21%), and stomatitis (20%).
CAPItello-291 The safety of TRUQAP was evaluated in CAPItello-291, a clinical trial including 288 adult patients (155 patients in TRUQAP with fulvestrant arm and 133 patients in placebo with fulvestrant arm) whose breast cancer had one or more PIK3CA/AKT1/PTEN -alterations [see Clinical Studies (14) ] . Among patients who received TRUQAP, 61% were exposed for 6 months or longer and 30% were exposed for greater than one year.
Of the 155 patients who received TRUQAP with fulvestrant, the median age was 58 years (range 36 to 84); female (99%); White (48%), Asian (31%), Black (1.3%), American Indian/Alaska Native (0.6%), and other races (19%). Serious adverse reactions occurred in 18% of patients receiving TRUQAP with fulvestrant. The most common serious adverse reactions (≥ 1%) were cutaneous adverse reaction (3.9%), diarrhea and pneumonia (2.6% each), vomiting and pyrexia (1.9% each), hyperglycemia, hypersensitivity, fatigue, renal injury and second malignancy (1.3% each).
Fatal adverse reactions occurred in 1.3% of patients who received TRUQAP with fulvestrant, including sepsis (0.6%), and acute myocardial infarction (0.6%). Permanent TRUQAP discontinuation due to an adverse reaction occurred in 10% of patients. The most common adverse reaction (≥ 2%) leading to permanent discontinuation of TRUQAP was cutaneous adverse reactions (6%). Dosage interruptions of TRUQAP due to an adverse reaction occurred in 39% of patients.
Adverse reactions leading to dosage interruption in ≥ 2% of patients included cutaneous adverse reactions (14%), diarrhea (10%), pyrexia (4.5%), vomiting and nausea (3.2% each), and fatigue (2.6%). Dose reductions of TRUQAP due to adverse reactions occurred in 21% of patients receiving TRUQAP with fulvestrant. Adverse reactions leading to TRUQAP dose reductions in ≥ 2% of patients were diarrhea and cutaneous adverse reactions (8% each).
The most common (≥ 20%) adverse reactions including laboratory abnormalities were diarrhea (77%), increased random glucose (58%), cutaneous adverse reaction (56%), decreased lymphocytes (49%), decreased hemoglobin (47%), fatigue (38%), increased fasting glucose (37%), nausea and decreased leukocytes (35% each), increased triglycerides (30%), stomatitis (25%), decreased neutrophils (25%), and vomiting (21%). Adverse reactions and laboratory abnormalities are listed in Table 4 and Table 5, respectively.
Table 4: Adverse Reactions ≥ 10% in Patients who Received TRUQAP with Fulvestrant [with a Difference Between Arms of ≥ 3%] in CAPItello-291 Adverse Reaction TRUQAP with Fulvestrant N=155 Placebo with Fulvestrant N=133 All Grades % Grade 3 or 4 % All Grades % Grade 3 or 4 % Gastrointestinal Disorders Diarrhea 77 12 19
0.8Skin and Subcutaneous Tissue Disorders
Cutaneous adverse reactions Cutaneous adverse reaction includes butterfly rash, dermatitis, allergic dermatitis, dry skin, eczema, erythema multiforme, hand dermatitis, palmar-plantar erythrodysesthesia syndrome, pruritus, rash, erythematous rash, maculo-papular rash, papular rash, skin discoloration, skin fissures, skin reaction, skin ulcer, urticaria, purpura, erythema and drug eruption. 56 15 16
0.8 Clinically relevant adverse reactions occurring in < 10% of patients treated with TRUQAP included anemia, pyrexia, dysgeusia, dyspepsia, pneumonia, weight decreased, and hypersensitivity (including anaphylactic reaction). Table 5: Laboratory Abnormalities (≥ 10%) That Worsened from Baseline in Patients who Received TRUQAP with Fulvestrant [With a Difference Between Arms ≥3%] in CAPItello-291 Laboratory Abnormality TRUQAP with Fulvestrant The denominator used to calculate the rate varied from 129 to 155 based on the number of patients with a baseline value and at least one post-treatment value.
Placebo with Fulvestrant The denominator used to calculate the rate varied from 109 to 131 based on the number of patients with a baseline value and at least one post-treatment value. All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Glucose Metabolism Increased random glucose 58 9 17 0 Increased fasting glucose 37 0.6 29 0 Hematology Decreased lymphocytes 49 11 14
