Komzifti

1 INDICATIONS AND USAGE KOMZIFTI is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible nucleophosmin 1 ( NPM1 ) mutation who have no satisfactory alternative treatment options [see Dosage and Administration ( 2.1 ), Clinical Pharmacology ( 12.1 ), and Clinical Studies ( 14 )] . KOMZIFTI is a menin inhibitor indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible nucleophosmin 1 ( NPM1 ) mutation who have no satisfactory alternative treatment options. ( 1 )

2 DOSAGE AND ADMINISTRATION Select patients for treatment with KOMZIFTI based on the presence of an NPM1 mutation. ( 2.1 ) Recommended dosage: 600 mg orally once daily until disease progression or unacceptable toxicity. For patients without confirmed disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for a clinical response. ( 2.2 ) See Full Prescribing Information for administration instructions and dosage modifications. ( 2.3 , 2.4 , 2.5 ) 2.1 Patient Selection Select patients for the treatment of relapsed or refractory AML with KOMZIFTI based on the presence of an NPM1 mutation [see Clinical Studies ( 14 )] . An FDA-approved test for the detection of NPM1 mutations is not currently available. 2.2 Recommended Dosage The recommended dosage of KOMZIFTI is 600 mg taken orally once daily until disease progression or unacceptable toxicity. Do not start KOMZIFTI until the white blood cell (WBC) count is reduced to less than 25 x 10⁹/L. For patients without confirmed disease progression or unacceptable toxicity, treatment for a minimum of 6 months is recommended to allow time for a clinical response. 2.3 Administration Instructions Administer KOMZIFTI once daily on an empty stomach (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology ( 12.3 )]. Administer KOMZIFTI orally at about the same time each day. Swallow capsules whole. Do not open, break, or chew the capsules. If a dose of KOMZIFTI is missed or not taken at the usual time, administer the dose as soon as possible on the same day and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day. Do not administer 2 doses within 12 hours. 2.4 Dosage Modifications for Concomitant Use of Acid-Reducing Agents Avoid concomitant use of proton pump inhibitors (PPIs) with KOMZIFTI. Avoid concomitant use of a histamine-2 (H2) receptor antagonist or a locally acting antacid with KOMZIFTI [see Drug Interactions ( 7.1 )] . If concomitant use cannot be avoided: Take KOMZIFTI 2 hours before or 10 hours after administration of an H2 receptor antagonist. Take KOMZIFTI 2 hours before or 2 hours after administration of a locally acting antacid. 2.5 Dosage Modifications for Adverse Reactions Manage any abnormalities promptly [see Warnings and Precautions ( 5.1 , 5.2 ) and Adverse Reactions ( 6.1 )] . Interrupt or reduce dose for adverse reactions as per Table 1 and Table 2 . Table 1 Recommended Management and Dosage Modifications for KOMZIFTI for Adverse Reactions Adverse Reaction a Recommended Action a Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. b Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening. c See Table 2 for the reduced dose levels. Differentiation syndrome [see Warnings and Precautions ( 5.1 )] If differentiation syndrome is suspected, interrupt KOMZIFTI. Administer systemic corticosteroids and initiate hemodynamic monitoring until symptom resolution and for a minimum of 3 days and provide supportive care. Resume KOMZIFTI at the same dose level when signs and symptoms improve and are Grade ≤ 2 b . Noninfectious leukocytosis (e.g., sudden or significant white blood cell (WBC) increase, including WBC doubling within the first 2 weeks of administration or an absolute increase of 10 x 10 9 /L) Evaluate for differentiation syndrome. Initiate treatment with hydroxyurea, as per standard institutional practices, and leukapheresis if clinically indicated. Taper hydroxyurea only after leukocytosis improves or resolves. Interrupt KOMZIFTI if leukocytosis is not controlled with hydroxyurea within 48 hours. If interrupted, resume KOMZIFTI at the same dose level once WBC counts are controlled. Nonhematological adverse reactions Grade ≥ 3 b [see Adverse Reactions ( 6.1 )] Interrupt KOMZIFTI until recovery to Grade ≤ 2 b . Resume KOMZIFTI at the same dose level. If the same Grade ≥ 3 toxicity recurs, interrupt KOMZIFTI until recovery to Grade ≤ 2 b . Restart KOMZIFTI at a reduced dose c . Table 2 Recommended Dosage Reductions for KOMZIFTI for Adverse Reactions *Permanently discontinue KOMZIFTI in patients unable to tolerate 200 mg orally once daily following second dose reduction. Recommended Dosage First dose reduction 400 mg orally once daily Second dose reduction 200 mg orally once daily

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS QTc Interval Prolongation: Monitor electrocardiograms and electrolytes. Correct hypokalemia and hypomagnesemia prior to treatment. Interrupt KOMZIFTI if the QTc interval is > 500 ms. ( 5.2 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.3 , 8.1 , 8.3 ) 5.1 Differentiation Syndrome KOMZIFTI can cause fatal or life-threatening differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells. Symptoms of differentiation syndrome, including those seen in patients treated with KOMZIFTI, may include fever, hypoxia, joint pain, hypotension, dyspnea, rapid weight gain or peripheral edema, pleural or pericardial effusions, acute kidney injury, and rashes. In the clinical trial, differentiation syndrome occurred in 29 (26%) of 112 patients with relapsed or refractory AML with an NPM1 mutation who were treated with KOMZIFTI at the recommended dosage. Differentiation syndrome was Grade 3 in 13% and fatal in two patients. In broader evaluation of all patients with any genetic form of AML treated with KOMZIFTI monotherapy in clinical trials, differentiation syndrome occurred in 25% of patients. Four fatal cases of differentiation syndrome occurred out of 39 patients with KMT2A -rearranged AML treated with KOMZIFTI. KOMZIFTI is not approved for use in patients with KMT2A -rearranged AML. In the 112 patients with an NPM1 mutation, differentiation syndrome was observed with and without concomitant hyperleukocytosis, in as early as 3 days and up to 46 days after KOMZIFTI initiation. The median time to onset was 15 days. Two patients experienced more than one differentiation syndrome event. Treatment was interrupted and resumed in 15 (13%) patients, while it was permanently discontinued in 2 (2%) patients [see Adverse Reactions ( 6.1 )] . Prior to starting treatment with KOMZIFTI, reduce the WBC counts to less than 25 x 10⁹/L. If differentiation syndrome is suspected, interrupt KOMZIFTI, initiate oral or intravenous corticosteroids (e.g., dexamethasone 10 mg every 12 hours) for a minimum of 3 days with hemodynamic and laboratory monitoring. Resume treatment with KOMZIFTI at the same dose level when signs and symptoms improve and are Grade 2 or lower. Taper corticosteroids over a minimum of 3 days after adequate control or resolution of symptoms [see Dosage and Administration ( 2.5 )] . Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment. 5.2 QTc Interval Prolongation KOMZIFTI can cause QT (QTc) interval prolongation [see Clinical Pharmacology ( 12.2 ) ] . In the clinical trial, QTc interval prolongation was reported as an adverse reaction in 12% of 112 patients treated with KOMZIFTI at the recommended dosage for relapsed or refractory AML with an NPM1 mutation. QTc interval prolongation was Grade 3 in 8% of patients. The heart-rate corrected QT interval (using Fridericia's method) (QTcF) was greater than 500 msec in 9% of patients, and the increase from baseline QTcF was greater than 60 msec in 12% of patients. KOMZIFTI dose reduction was required for 1% of patients due to QTc interval prolongation [see Adverse Reactions ( 6.1 )] . QTc prolongation occurred in 14% of the 42 patients less than 65 years of age and in 10% of the 70 patients 65 years of age or older. Correct electrolyte abnormalities, including hypokalemia and hypomagnesemia, prior to treatment with KOMZIFTI. Perform an ECG prior to initiation of treatment with KOMZIFTI, and do not initiate KOMZIFTI in patients with QTcF > 480 msec. Perform an ECG at least once weekly for the first four weeks on treatment, and at least monthly thereafter. Interrupt KOMZIFTI if the QTc interval is > 500 ms or the change from baseline is > 60 ms (Grade 3) [see Dosage and Administration ( 2.5 )] . In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent ECG monitoring may be necessary. Concomitant use of KOMZIFTI with drugs known to prolong the QTc interval may increase the risk of QTc interval prolongation [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.2 )] . 5.3 Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, KOMZIFTI can cause embryo-fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of ziftomenib to pregnant mice during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, structural abnormalities, and altered fetal growth at approximately 0.3 times the steady-state clinical exposure based on the area under the concentration-time curve (AUC) at the recommended human dose. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with KOMZIFTI and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with KOMZIFTI and for 3 months after the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] .

7 DRUG INTERACTIONS Strong or Moderate CYP3A4 Inhibitors: Monitor more frequently for adverse reactions. ( 7.1 ) Strong or Moderate CYP3A4 Inducers: Avoid concomitant use. ( 7.1 ) Proton Pump Inhibitors: Avoid concomitant use. ( 2.4 , 7.1 ) H2 Receptor Antagonists and Antacids: Avoid concomitant use. If concomitant use cannot be avoided, modify KOMZIFTI administration time. ( 2.4 , 7.1 ) Drugs that Prolong the QTc Interval: Avoid concomitant use. If concomitant use is unavoidable, monitor patients more frequently for QTc interval prolongations. ( 5.2 , 7.1 ) 7.1 Effect of Other Drugs on KOMZIFTI Strong or Moderate CYP3A4 Inhibitors Monitor patients more frequently for KOMZIFTI-associated adverse reactions. Ziftomenib is primarily metabolized by CYP3A. Concomitant use of KOMZIFTI with strong or moderate CYP3A4 inhibitors increases ziftomenib exposure [see Clinical Pharmacology ( 12.3 )], which may increase the risk of adverse reactions such as QT prolongation. Strong or Moderate CYP3A4 Inducers Avoid concomitant use of KOMZIFTI with strong or moderate CYP3A4 inducers. Ziftomenib is primarily metabolized by CYP3A. Concomitant use of KOMZIFTI with strong or moderate CYP3A4 inducers may decrease ziftomenib exposure [see Clinical Pharmacology ( 12.3 )] , which may reduce the efficacy of KOMZIFTI. Gastric Acid Reducing Agents Concomitant administration of ziftomenib with proton pump inhibitors (PPIs) decreases ziftomenib exposure [see Clinical Pharmacology ( 12.3 )] , which may reduce the efficacy of KOMZIFTI. Avoid concomitant use of KOMZIFTI with PPIs. Avoid concomitant use of KOMZIFTI with H2 receptor antagonists (H2RAs) or locally acting antacids. If concomitant use cannot be avoided, modify KOMZIFTI administration time [see Dosage and Administration ( 2.4 )] . Drugs that Prolong the QT Interval Avoid concomitant use of KOMZIFTI with other product(s) with a known potential to prolong the QTc interval. If concomitant use cannot be avoided, obtain ECGs when initiating, during concomitant use, and as clinically indicated [see Warnings and Precautions ( 5.2 )] . Interrupt KOMZIFTI if the QTc interval is > 500 ms or the change from baseline is > 60 ms [see Dosage and Administration ( 2.5 )] . Ziftomenib causes QTc interval prolongation [see Clinical Pharmacology ( 12.2 )] . Concomitant use of KOMZIFTI with other products that prolong the QTc interval may result in a greater increase in the QTc interval and adverse reactions associated with QTc interval prolongation, including Torsades de pointes, other serious arrhythmias, and sudden death [see Warnings and Precautions ( 5.2 )] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Differentiation Syndrome [see Warnings and Precautions ( 5.1 )] QTc Interval Prolongation [see Warnings and Precautions ( 5.2 )] The most common adverse reactions (≥20%) are infection without an identified pathogen, hemorrhage, diarrhea, nausea, fatigue, edema, bacterial infection, musculoskeletal pain, differentiation syndrome, pruritus, febrile neutropenia, and transaminases increased. ( 6.1 ) The most common laboratory abnormalities (≥10%) are aspartate aminotransferase increased, potassium decreased, albumin decreased, alanine aminotransferase increased, sodium decreased, creatinine increased, alkaline phosphatase increased, bilirubin increased, potassium increased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Kura Oncology, Inc., at 1-844-KURAONC, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical 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. Relapsed or Refractory AML with an NPM1 Mutation The safety of KOMZIFTI for the treatment of patients with relapsed or refractory AML with an NPM1 mutation was evaluated in KO-MEN-001 [see Clinical Studies ( 14 )] . Patients received KOMZIFTI 600 mg once daily (n=112). The median duration of exposure to KOMZIFTI was 2.2 months (range 0.1 to 21.5 months). Fatal adverse reactions occurred in 4 (4%) patients who received KOMZIFTI, including 2 with differentiation syndrome, 1 with infection, and 1 with sudden death. Serious adverse reactions were reported in 79% of patients who received KOMZIFTI. Serious adverse reactions occurring in ≥ 5% of patients included infection without an identified pathogen (29%), febrile neutropenia (18%), bacterial infection (16%), differentiation syndrome (16%), and dyspnea (6%). Dosage interruption of KOMZIFTI due to an adverse reaction occurred in 54% of patients. Adverse reactions that required dose interruption in ≥ 2% of patients included infection without an identified pathogen (15%), differentiation syndrome (13%), febrile neutropenia (5%), pyrexia (4%), electrocardiogram QT prolonged (4%), leukocytosis (4%), bacterial infection (3%), cardiac failure (2%), cholecystitis (2%), diarrhea (2%), pruritus (2%), and thrombosis (2%). Dose reduction of KOMZIFTI due to an adverse reaction occurred in 4% of patients. Permanent discontinuation of KOMZIFTI due to an adverse reaction occurred in 21% of patients. Adverse reactions that required permanent discontinuation of KOMZIFTI in ≥ 2% of patients were infection without an identified pathogen (8%), bacterial infection (4%), cardiac arrest (2%), and differentiation syndrome (2%). The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were aspartate aminotransferase increased, infection without an identified pathogen, potassium decreased, albumin decreased, alanine aminotransferase increased, sodium decreased, creatinine increased, alkaline phosphatase increased, hemorrhage, diarrhea, nausea, fatigue, edema, bacterial infection, musculoskeletal pain, bilirubin increased, potassium increased, differentiation syndrome, pruritus, febrile neutropenia, and transaminases increased. Table 3 summarizes the adverse reactions in KO-MEN-001. Table 3 Adverse Reactions Reported in ≥20% (Any Grade) or ≥5% (Grade 3 or 4) of Patients with Relapsed or Refractory AML †Includes the following fatal adverse reactions: infection (n=1) and differentiation syndrome (n=2). *No Grade 4 events were reported for this adverse reaction. a Includes abdominal abscess, abscess limb, anal abscess, anorectal infection, bronchitis, conjunctivitis, device related infection, device related sepsis, diverticulitis, emphysematous cystitis, enterocolitis infectious, gingivitis, hordeolum, infection, large intestine infection, nail infection, necrotizing fasciitis, penile infection, periodontitis, perirectal abscess, peritonitis, pneumonia, postoperative abscess, respiratory tract infection, rhinitis, sepsis, septic shock, sinusitis, skin infection, soft tissue infection, tooth infection, upper respiratory tract infection, urosepsis, vaginal infection, vascular device infection, wound infection. b Includes bacteremia, bacterial infection, bacterial pyelonephritis, breast cellulitis, cellulitis, clostridial infection, clostridium difficile colitis, clostridium difficile infection, enterobacter sepsis, enterococcal bacteremia, erysipelas, escherichia bacteremia, escherichia infection, escherichia sepsis, escherichia urinary tract infection, klebsiella bacteremia, klebsiella infection, klebsiella urinary tract infection, paronychia, pneumonia bacterial, pneumonia klebsiella, pseudomonal bacteremia, staphylococcal bacteremia. c Includes adenovirus infection, COVID-19, genital herpes, herpes simplex reactivation, herpes virus infection, herpes zoster, nasal herpes, oral herpes, pneumonia influenzas, pneumonia parainfluenza viral, respiratory syncytial virus infection, rhinovirus infection. d Includes angina bullosa hemorrhagic, bladder tamponade, catheter site hematoma, conjunctival hemorrhage, contusion, disseminated intravascular coagulation, ecchymosis, epistaxis, gastric hemorrhage, gastrointestinal hemorrhage, gingival bleeding, hematemesis, hematochezia, hematoma, hematuria, hemoptysis, hemorrhage, hemorrhoidal hemorrhage, hyperfibrinolysis, injection site hematoma, injection site hemorrhage, lower gastrointestinal hemorrhage, melaena, mouth hemorrhage, oral blood blister, petechiae, purpura, rectal hemorrhage, retinal hemorrhage, shock hemorrhagic, skin hemorrhage, subdural hematoma, tongue hemorrhage, traumatic hematoma, upper gastrointestinal hemorrhage, vaginal hemorrhage, vitreous hemorrhage. e Includes diarrhea, colitis, colitis erosive. f Includes nausea, vomiting. g Includes fatigue, asthenia, malaise. h Includes edema, edema peripheral, generalized edema, localized edema, peripheral swelling. i Includes arthralgia, back pain, bone pain, flank pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, pain in extremity. j Includes pruritus, nasal pruritus. k Includes white blood cell count increased, leukocytosis, hyperleukocytosis. l Includes transaminases increased, alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyl transferase increased, hypertransaminasemia. m Includes renal impairment: acute kidney injury, azotemia, blood creatinine increased, blood urea increased, chronic kidney disease, postrenal failure, renal failure. Adverse Reaction KOMZIFTI N=112 All Grades † (%) Grade 3 or 4 (%) Infections and infestations Infection without identified pathogen a 52 38 Bacterial infection b 28 17 Viral infection c 16 5 Vascular disorders Hemorrhage d 38 8 Hypertension 11 5 Gastrointestinal disorders Diarrhea e* 36 5 Nausea f* 35 2 General disorders and administration site conditions Fatigue g 34 8 Edema h* 30 3 Musculoskeletal and connective tissue disorders Musculoskeletal pain i 28 4 Neoplasms benign, malignant, and unspecified (incl cysts and polyps) Differentiation syndrome 26 13 Skin and subcutaneous Pruritus j* 23 0 Blood and lymphatic system disorder Febrile neutropenia 22 22 Leukocytosis k* 16 5 Investigations Transaminases increased l 21 8 Electrocardiogram QT prolonged * 12 8 Renal and urinary disorders Renal impairment m 19 6 Respiratory, thoracic, and mediastinal disorders Hypoxia 9 5 Table 4 summarizes the laboratory abnormalities in KO-MEN-001. Table 4 Selected New or Worsening Laboratory Abnormalities in Patients with Relapsed or Refractory AML *The denominator used to calculate the rate varied from 108 to 110 based on the number of patients with a baseline value and at least one post-baseline value. Laboratory Abnormality KOMZIFTI Grades 1-4* (%) Grade 3-4* (%) Aspartate aminotransferase increased 53 4 Potassium decreased 52 22 Albumin decreased 51 5 Alanine aminotransferase increased 50 6 Sodium decreased 49 3 Creatinine increased 45 4 Alkaline phosphatase increased 41 5 Bilirubin increased 27 6 Potassium increased 26 6

8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action [see Clinical Pharmacology ( 12.1 )] , KOMZIFTI can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on KOMZIFTI use in pregnant women to evaluate for a drug-associated risk. In animal reproduction studies, oral administration of ziftomenib to pregnant mice during the period of organogenesis resulted in adverse developmental outcomes, including embryo-fetal mortality, structural abnormalities, and altered fetal growth at maternal exposures approximately 0.3 times the human exposure (AUC) at the recommended dose (see Data ) . Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Ziftomenib was administered orally twice daily to pregnant mice at doses of 6, 20, and 60 mg/kg/day during organogenesis (gestation days 6-15). Decreased fetal body weight, embryo-fetal lethality, fetal external and skeletal malformations and variations (cleft palate, fused cervical arches, absent lumbar vertebrae fused and/or misaligned costal cartilage, absent or short rib, supernumerary site in the suture bone or split palatine of the skull, and/or fused, unossified, and/or incompletely ossified sternebrae) were noted at all doses. At the dose of 6 mg/kg/day in mice, the maternal exposure was approximately 0.3 times the human exposure at the recommended dose of 600 mg once daily.