FYARRO - Aadi Bioscience, Inc.

The recommended dosage of FYARRO is 100 mg/m² administered as an intravenous infusion over 30 minutes on Days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity.

Table 1 lists the recommended dose reductions of FYARRO for adverse reactions.

Table 2 lists the recommended dosage modifications of FYARRO for adverse reactions.

Avoid concomitant use with strong CYP3A inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Reduce the dosage of FYARRO to 56 mg/m² on days 1 and 8 of every 21-day cycle when used concomitantly with a moderate or weak CYP3A inhibitor.

Avoid use in patients with severe hepatic impairment (total bilirubin >3 ULN and any AST) [see Use in Specific Populations (8.6)].

The recommended dosage of FYARRO in patients with mild or moderate hepatic impairment is described in Table 3 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. Monitor patients with hepatic impairment for increased adverse reactions.

FYARRO is a hazardous drug. Follow applicable special handling and disposal procedures.¹

FYARRO is supplied as a sterile lyophilized powder for reconstitution before use. READ ENTIRE PREPARATION INSTRUCTIONS PRIOR TO RECONSTITUTION.

Unopened vials of FYARRO are stable until the date indicated on the package when stored between 2ºC to 8ºC (36ºF to 46ºF) in the original package. Neither freezing nor thawing adversely affects the stability of the product.

Stomatitis, including mouth ulcers and oral mucositis, occurred in 79% of patients treated with FYARRO, including 18% Grade 3. Stomatitis was most often first reported within 8 weeks of treatment. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO [see Dosage and Administration (2.2), Adverse Reactions (6.1)].

FYARRO can cause myelosuppression including anemia, thrombocytopenia and neutropenia. Anemia occurred in 68% of patients; 6% were Grade 3. Thrombocytopenia and neutropenia occurred in 35% of patients each.

Obtain blood counts at baseline and every 2 months for the first year of treatment and every 3 months thereafter, or more frequently if clinically indicated. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO [see Dosage and Administration (2.2), Adverse Reactions (6.1)].

FYARRO can cause infections. Infections such as urinary tract infections (UTI), upper respiratory tract infections and sinusitis occurred in 59% of patients. Grade 3 infections occurred in 12% of patients, including a single case each of a UTI, pneumonia, skin, and abdominal infections. Monitor patients for infections, including opportunistic infections. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO [see Dosage and Administration (2.2), Adverse Reactions (6.1)].

FYARRO can cause hypokalemia. Hypokalemia occurred in 44% of patients, including 12% Grade 3 events. Monitor potassium levels prior to starting FYARRO and implement potassium supplementation as medically indicated. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO [see Dosage and Administration (2.2), Adverse Reactions (6.1)].

FYARRO can cause hyperglycemia. Hyperglycemia occurred in 12% of patients treated with

FYARRO, all of which were Grade 3 events. Monitor fasting serum glucose prior to starting FYARRO. During treatment, monitor serum glucose every 3 months in non-diabetic patients, or as clinically indicated. Monitor serum glucose more frequently in diabetic patients. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO [see Dosage and Administration (2.2), Adverse Reactions (6.1)].

FYARRO can cause interstitial lung disease (ILD) / non-infectious pneumonitis. ILD / non-infectious pneumonitis occurred in 18% of patients treated with FYARRO, of which all were Grades 1 or 2. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO [see Dosage and Administration (2.2)].

FYARRO can cause serious and sometimes fatal hemorrhage. Hemorrhage occurred in 24% of patients treated with FYARRO, including Grade 3 and Grade 5 events in 2.9% of patients each [see Adverse Reactions (6.1)]. Monitor patients for signs and symptoms of hemorrhage. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO [see Dosage and Administration (2.2)].

FYARRO can cause hypersensitivity reactions [see Contraindications (4)].

• Hypersensitivity reactions, including anaphylactic, angioedema, exfoliative dermatitis and hypersensitivity vasculitis have been observed with administration of the oral formulation of sirolimus.
• Hypersensitivity reactions including anaphylaxis have been observed with human albumin administration.

Monitor patients closely for signs and symptoms of infusion reactions during and following each FYARRO infusion in a setting where cardiopulmonary resuscitation medication and equipment are available. Monitor patients for at least 2 hours after the first infusion and as clinically needed for each subsequent infusion.

Reduce the rate, interrupt infusion, or permanently discontinue FYARRO based on severity and institute appropriate medical management as needed.

Based on animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], FYARRO can cause fetal harm when administered to a pregnant woman. In animal studies, mechanistic target of rapamycin kinase (mTOR) inhibitors caused embryo-fetal toxicity when administered during the period of organogenesis at maternal exposures that were equal to or less than human exposures at the recommended lowest starting dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to avoid becoming pregnant and to use effective contraception while using FYARRO and for 12 weeks after the last dose [see Use in Specific Populations (8.1, 8.3)].

Azoospermia or oligospermia may be observed in patients treated with FYARRO [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)]. FYARRO is an anti-proliferative drug and affects rapidly dividing cells such as germ cells.

No studies in conjunction with immunization have been conducted with FYARRO. Immunization during FYARRO treatment may be ineffective. Update immunizations according to immunization guidelines prior to initiating FYARRO, if possible. Immunization with live vaccines is not recommended during treatment and avoid close contact with those who have received live vaccines while on FYARRO. The interval between live vaccinations and initiation of FYARRO should be in accordance with current vaccination guidelines for patients on immunosuppressive therapies.

FYARRO contains human albumin, a derivative of human blood. Human albumin carries only a remote risk of transmission of viral diseases because of effective donor screening and product manufacturing processes. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been associated with albumin.

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 of FYARRO was assessed in a single-arm study (AMPECT). Thirty-four patients received FYARRO 100 mg/m² on Days 1 and 8 of 21-day cycles until disease progression or unacceptable toxicity [see Clinical Studies (14.1)]. Among the 34 patients who received FYARRO, 16 (47%) were exposed for 6 months or longer and 7 (21%) were exposed for greater than 1 year.

The median age of patients who received FYARRO was 59.5 years (range 27 to 78 years), 82% were female and Eastern Cooperative Oncology Group (ECOG) Performance Status was 0 (76%) or 1 (24%). Race was 71% White, 9% Black, 9% Asian, 3% Hawaiian/Pacific Islander and 9% Other/Not Reported. Ethnicity was 82% not Hispanic or Latino, 15% Hispanic or Latino, and 3% Not Reported.

Serious adverse reactions occurred in 14 (41%) patients who received FYARRO. Serious adverse reactions in >5% of patients, including 4 (12%) patients with infection and 2 (6%) patients each with abdominal pain, dehydration, and upper gastrointestinal hemorrhage. Fatal adverse reactions occurred in 1 (2.9%) patient who received FYARRO and experienced upper gastrointestinal hemorrhage.

Permanent discontinuation of FYARRO due to an adverse reaction occurred in 3 (9%) patients. Adverse reactions which resulted in permanent discontinuation of FYARRO included pneumonitis, anemia, and noninfective cystitis.

Dosage interruptions of FYARRO due to an adverse reaction occurred in 22 (65%) patients. Adverse reactions which required dosage interruption in >5% of patients included stomatitis in 6 (18%) patients, pneumonitis in 5 (15%) patients, anemia in 3 (9%) patients, and dehydration, dermatitis acneiform, and thrombocytopenia in 2 (6%) patients each.

Dose reductions of FYARRO due to an adverse reaction occurred in 12 (35%) patients. Adverse reactions which required dose reductions in >5% of patients included stomatitis and pneumonitis in 3 (9%) patients each.

The most common adverse reactions (≥30%) were stomatitis in 27 (79%) patients, fatigue and rash in 23 (68%) patients each, infection in 20 (59%) patients, nausea and edema in 17 (50%) patients each, diarrhea, musculoskeletal pain and decreased weight in 16 (47%) patients each, decreased appetite in 15 (44%) patients, cough in 12 (35%) patients, and vomiting and dysgeusia in 11 (32%) patients each. The most common Grade 3 to 4 laboratory abnormalities (≥6%) were decreased lymphocytes in 7 (21%) patients, increased glucose and decreased potassium in 4 (12%) patients each, decreased phosphate in 3 (9%) patients, and decreased hemoglobin and increased lipase in 2 (6%) patients each.

Table 4 summarizes the adverse reactions in AMPECT.

Table 5 summarizes the laboratory abnormalities in AMPECT.

Clinically relevant adverse reactions occurring in <10% of patients included enteritis, edema, pancytopenia, acute kidney injury, and acute coronary syndrome.

FYARRO can cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.9), Use in Specific Populations (8.1)].

The safety and efficacy of FYARRO in pediatric patients have not been established.

Of the 34 patients treated with FYARRO, 44% were 65 years of age and older, and 6% were 75 years of age and older. Clinical studies of FYARRO did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

Avoid use in patients with severe hepatic impairment.

Reduce FYARRO dosage in patients with mild or moderate hepatic impairment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

Sirolimus in FYARRO is an inhibitor of mechanistic target of rapamycin kinase (mTOR, previously known as mammalian target of rapamycin). mTOR, a serine threonine kinase, is downstream of the PI3K/AKT pathway, controls key cellular processes such as cell survival, growth, and proliferation, and is commonly dysregulated in several human cancers. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex. The sirolimus-FKBP-12 complex binds to and inhibits activation of the mechanistic target of rapamycin complex 1 (mTORC1). Inhibition of mTOR by sirolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and in vivo studies. In a nonclinical study in athymic mice bearing human tumor xenografts, intravenous administration of FYARRO resulted in higher tumor accumulation of sirolimus, inhibition of an mTOR target in the tumor, and tumor growth inhibition compared to administration of an oral formulation of sirolimus at the same weekly total dose.

Sirolimus exposure-response relationship has not been fully characterized.

At the recommended dosage, the estimated sirolimus mean (coefficient of variation [CV] %) maximum concentration (Cmax) is 2,590 ng/mL (30%) and AUC is 22,100 ng∙h/mL (50%) in patients with advanced solid tumors.

No carcinogenicity, mutagenesis, or fertility studies were conducted with FYARRO.

Carcinogenicity studies have been conducted in mice and rats with an oral formulation of sirolimus. In an 86-week female mouse study, there was a statistically significant increase in malignant lymphoma at all dose levels compared with controls. In a second mouse study, hepatocellular adenoma and carcinoma in males were considered sirolimus-related. In a 104-week rat study, there were no significant findings.

Sirolimus was not genotoxic in an in vitro bacterial reverse mutation assay, a Chinese hamster ovary cell chromosomal aberration assay, a mouse lymphoma cell forward mutation assay, or an in vivo mouse micronucleus assay.

When female rats were treated by gavage with an oral formulation of sirolimus and mated to untreated males, female fertility was decreased at 0.5 mg/kg due to decreased implantation. In addition, reduced ovary and uterus weight were observed. The NOAEL for female rat fertility was 0.1 mg/kg.

When male rats were treated by gavage with an oral formulation of sirolimus and mated to untreated females, male fertility was decreased at 2 mg/kg. Atrophy of testes, epididymides, prostate, seminiferous tubules, and reduced sperm counts were observed. The NOAEL for male rat fertility was 0.5 mg/kg.

Testicular tubular degeneration was also seen in a 4-week intravenous study of sirolimus in monkeys at 0.1 mg/kg.

The efficacy of FYARRO was assessed in AMPECT (NCT02494570), a multi-center, single-arm clinical trial in 31 patients with locally advanced unresectable or metastatic malignant PEComa. Patients were required to have measurable disease at baseline, centrally confirmed diagnosis by pathology of malignant PEComa, and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1. Patients with lymphangioleiomyomatosis and prior treatment with a mTOR inhibitor were excluded. Patients received FYARRO at a dose of 100 mg/m² on Days 1 and 8 of 21day cycles until disease progression or unacceptable toxicity.

The efficacy population of 31 patients had the following demographic characteristics: median age 60 years (range 34 to 78), 81% female, 74% White, 10% Black, and 81% ECOG PS of 0. Five (16%) patients had locally advanced disease and 26 (84%) had metastatic disease. Ninety-four percent of patients had prior surgery,19% had prior radiation therapy, and 13% had prior systemic therapy.

The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR) as assessed by blinded independent central review (BICR) using RECIST v.1.1.

The efficacy results are summarized in Table 6.

Stomatitis

Advise patients of the risk of stomatitis [see Warnings and Precautions (5.1)].

Myelosuppression

Advise patients of the risk of myelosuppression and the need to monitor blood counts periodically during therapy [see Warnings and Precautions (5.2)].

Infections

Advise patients that they are more susceptible to infections and that they should immediately report any signs or symptoms of infection to their healthcare provider [see Warnings and Precautions (5.3)].

Hypokalemia

Advise patients of the risk of hypokalemia and the need to monitor potassium periodically during therapy [see Warnings and Precautions (5.4)].

Hyperglycemia

Advise patients of the risk of hyperglycemia and the need to monitor glucose periodically during therapy [see Warnings and Precautions (5.5)].

Interstitial Lung Disease / Non-Infectious Pneumonitis

Advise patients of the risk of developing non-infectious pneumonitis and to immediately report any new or worsening respiratory symptoms to their healthcare provider [see Warnings and Precautions (5.6)].

Hemorrhage

Advise patients of the risk of hemorrhage. Instruct patients to report signs of bleeding, and to seek immediate medical attention for signs or symptoms of severe bleeding [see Warnings and Precautions (5.7)].

Hypersensitivity Reactions

Advise patients of the risk of clinically significant hypersensitivity reactions and to promptly contact their healthcare provider or seek emergency care for signs of hypersensitivity reaction including rash, itching, hives, difficulty breathing or swallowing, flushing, chest pain, or dizziness [see Contraindications (4), Warnings and Precautions (5.8)].

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.9)]. Advise females of reproductive potential to use effective contraception during treatment and for 12 weeks after the last dose [see Use in Specific Populations (8.1, 8.3)].

Advise males with female partners of reproductive potential to use effective contraception during treatment and for 12 weeks after the last dose [see Warnings and Precautions (5.9), Use in Specific Populations (8.3)].

Infertility

Advise males and females of reproductive potential of the potential risk for impaired fertility [see Warnings and Precautions (5.10), Use in Specific Populations (8.3)].

Immunizations

Advise patients that vaccinations may be less effective while being treated with FYARRO. Advise patients to avoid the use of live vaccines, and close contact with those who have received live vaccines, while on FYARRO [see Warnings and Precautions (5.11)].

Lactation

Advise women not to breastfeed during treatment with FYARRO and for 2 weeks after the last dose [see Use in Specific Populations (8.2)].

Drug Interactions

Advise patients to inform their healthcare provider about all concomitant medications, including prescription medicine, over the counter drugs, vitamins, and herbal products [see Drug Interactions (7)]. Inform patients to avoid grapefruit and grapefruit juice while taking FYARRO.

This product's label may have been updated. For current full prescribing information, please visit www.aadibio.com.

Manufactured for Aadi Bioscience, Inc., Morristown, NJ 07960.
FYARRO ^® is a registered trademark of Aadi Bioscience, Inc.
Patent: www.aadibio.com/patents