Ixempra Drug Information
Generic name: IXABEPILONE
Uses of Ixempra
is indicated in combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated. Anthracycline resistance is defined as progression while on therapy or within 6 months in the adjuvant setting or 3 months in the metastatic setting. Taxane resistance is defined as progression while on therapy or within 12 months in the adjuvant setting or 4 months in the metastatic setting.
IXEMPRA is indicated as a single agent for the treatment of patients with metastatic or locally advanced breast cancer whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine. IXEMPRA is a microtubule inhibitor indicated for treatment: In combination with capecitabine for patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated.. As a single agent for patients with metastatic or locally advanced breast cancer after failure of an anthracycline, a taxane, and capecitabine..
Dosage & Administration of Ixempra
| aToxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events(CTCAE v3.0). | ||
|---|---|---|
| Grade 2 neuropathy (moderate) lasting ≥7 days | Decrease the dose by 20% | |
| Grade 3 neuropathy (severe) lasting <7 days | Decrease the dose by 20% | |
| Grade 3 neuropathy (severe) lasting ≥7 days or disabling neuropathy | Discontinue treatment | |
| Any grade 3 toxicity (severe) other than neuropathy | Decrease the dose by 20% | |
| Transient grade 3 arthralgia/myalgia or fatigue | No change in dose of IXEMPRA | |
| Grade 3 hand-foot syndrome (palmar-plantar erythrodysesthesia) | ||
| Any grade 4 toxicity (disabling) | Discontinue treatment | |
| Neutrophil <500 cells/mm 3 for ≥7 days | Decrease the dose by 20% | |
| Febrile neutropenia | Decrease the dose by 20% | |
| Platelets <25,000/mm 3 or platelets <50,000/mm 3 with bleeding | Decrease the dose by 20% | |
| See capecitabine prescribing information | ||
| Platelets <25,000/mm 3 or <50,000/mm 3 with bleeding | Hold for concurrent diarrhea or | |
| stomatitis until platelet count >50,000/mm 3, | ||
| then continue at same dose. | ||
| Neutrophils <500 cells/mm 3 for ≥7 days or febrile neutropenia | Hold for concurrent diarrhea or | |
| stomatitis until neutrophil count >1,000 cells/mm 3, | ||
| then continue at same dose. | ||
Side Effects of Ixempra
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. Unless otherwise specified, assessment of adverse reactions is based on one randomized study (Study 046) and one single-arm study (Study 081). In Study 046, 369 patients with metastatic breast cancer were treated with IXEMPRA 40 mg/m 2 administered intravenously over 3 hours every 21 days, combined with capecitabine 1000 mg/m 2 twice daily for 2 weeks followed by a 1-week rest period. Patients treated with capecitabine as a single agent (n=368) in this study received 1250 mg/m twice daily for 2 weeks every 21 days.
In Study 081, 126 patients with metastatic or locally advanced breast cancer were treated with IXEMPRA 40 mg/m 2 administered intravenously over 3 hours every 3 weeks. The most common adverse reactions (≥20%) reported by patients receiving IXEMPRA were peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain. The following additional reactions occurred in ≥20% in combination treatment: palmar-plantar erythrodysesthesia (hand-foot) syndrome, anorexia, abdominal pain, nail disorder, and constipation.
The most common hematologic abnormalities (>40%) include neutropenia, leukopenia, anemia, and thrombocytopenia. Table 4 presents nonhematologic adverse reactions reported in 5% or more of patients. Hematologic abnormalities are presented separately in Table 5. Table 4 presents nonhematologic adverse reactions reported in 5% or more of patients.
Hematologic abnormalities are presented separately in Table 5. b A composite of multiple terms. c Three patients (1 %) experienced Grade 5 (fatal) febrile neutropenia. Other neutropenia-related deaths occurred in the absence of reported febrile neutropenia. d No grade 4 reports. e Peripheral sensory neuropathy was defined as the occurrence of any of the following: areflexia, burning sensation, dysesthesia, hyperesthesia, hypoesthesia, hyporeflexia, neuralgia, neuritis, neuropathy, neuropathy peripheral, neurotoxicity, painful response to normal stimuli, paresthesia, pallanesthesia, peripheral sensory neuropathy, polyneuropathy, polyneuropathy toxic and sensorimotor disorder. Peripheral motor neuropathy was defined as the occurrence of any of the following: multifocal motor neuropathy, neuromuscular toxicity, peripheral motor neuropathy, and peripheral sensorimotor neuropathy. f Palmar-plantar erythrodysesthesia (hand-foot syndrome) was graded on a 1 -3 severity scale in Study 046. Study 046 Study 081 IXEMPRA with capecitabine n=369 Capecitabine n=368 IXEMPRA Single Agent n=126 Adverse Reaction All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Preferred Term (%) (%) (%) (%) (%) (%) Infections and Infestations Upper respiratory tract infection 4 0 3 0 6 0 Blood and Lymphatic System Disorders 1 d 3 d Febrile neutropenia 5 4 c 1 3 Immune System Disorders 1 d Hypersensitivity b 2 1 d 0 0 5 Metabolism and Nutrition Disorders Anorexia b 34 3 d 15 1 d 19 2 d Dehydration b 5 2 2 <1 d 2 1 d Psychiatric Disorders Insomnia b 9 <1 d 2 0 5 0 Nervous System Disorders Peripheral neuropathy Sensory neuropathy b 65 21 16 0 62 14 Motor neuropathy b 16 5 d <1 0 10 1 d Headache 8 <1 d 3 0 11 0 Taste disorder b 12 0 4 0 6 0 Dizziness 8 1 d 5 1 d 7 0 Eye Disorders Lacrimation increased 5 0 4 <1 d 4 0 Vascular Disorders Hot flush b 5 0 2 0 6 0 Respiratory, Thoracic, and Mediastinal Disorders Dyspnea b 7 1 4 1 9 1 d Cough b 6 0 2 0 2 0 Gastrointestinal Disorders Nausea 53 3 d 40 2 d 42 2 d Vomiting b 39 4 d 24 2 29 1 d Stomatitis/mucositis b 31 4 20 3 d 29 6 Diarrhea b 44 6 d 39 9 22 1 d Constipation 22 0 6 <1 d 16 2 d Abdominal pain b 24 2 d 14 1 d 13 2 d Gastroesophageal reflux disease b 7 1 d 8 0 6 0 Skin and Subcutaneous Tissue Disorders Alopecia b 31 0 3 0 48 0 Skin rash b 17 1 d 7 0 9 2 d Nail disorder b 24 2 d 10 <1 d 9 0 Palmar-plantar erythrodysesthesia syndrome b 64 18 d 63 17 d 8 2 d Pruritus 5 0 2 0 6 1 d Skin exfoliation b 5 <1 d 3 0 2 0 Skin hyperpigmentation b 11 0 14 0 2 0 Musculoskeletal, Connective Tissue, and Bone Disorders Myalgia/arthralgia b 39 8 d 5 <1 d 49 8 d Musculoskeletal pain b 23 2 d 5 0 20 3 d General Disorders and Administration Site Conditions Fatigue/asthenia b 60 16 29 4 56 13 Edema b 8 0 5 <1 d 9 1 d Pyrexia 10 1 d 4 0 8 1 d Pain b 9 1 d 2 0 8 3 d Chest pain b 4 1 d <1 0 5 1 d Investigations Weight decreased 11 0 3 0 6 0 Table 5: Hematologic Abnormalities in Patients with Metastatic or Locally Advanced Breast Cancer Treated with IXEMPRA a G-CSF (granulocyte colony stimulating factor) or GM-CSF (granulocyte macrophage colony stimulating factor) was used in 20% and 17% of patients who received IXEMPRA in Study 046 and Study 081, respectively.
Study 046 Study 081 IXEMPRA with capecitabine n=369 Capecitabine n=368 IXEMPRA single agent n=126 Hematology Parameter Grade 3 (%) Grade 4 (%) Grade 3 (%) Grade 4 (%) Grade 3 (%) Grade 4 (%) Neutropenia a 32 36 9 2 31 23 Leukopenia (WBC) 41 16 5 1 36 13 Anemia (Hgb) 8 2 4 1 6 2 Thrombocytopenia 5 3 2 2 5 2 The following serious adverse reactions were also reported in 1323 patients treated with IXEMPRA as single agent or in combination with other therapies in clinical studies. Infections and Infestations: sepsis, pneumonia, infection, neutropenic infection, urinary tract infection, bacterial infection, enterocolitis, laryngitis, lower respiratory tract infection Blood and Lymphatic System Disorders: coagulopathy, lymphopenia Metabolism and Nutrition Disorders: hyponatremia, metabolic acidosis, hypokalemia, hypovolemia Nervous System Disorders: cognitive disorder, syncope, cerebral hemorrhage, abnormal coordination, lethargy Cardiac Disorders: myocardial infarction, supraventricular arrhythmia, left ventricular dysfunction, angina pectoris, atrial flutter, cardiomyopathy, myocardial ischemia Vascular Disorders: hypotension, thrombosis, embolism, hemorrhage, hypovolemic shock, vasculitis Respiratory, Thoracic, and Mediastinal Disorders: pneumonitis, hypoxia, respiratory failure, acute pulmonary edema, dysphonia, pharyngolaryngeal pain Gastrointestinal Disorders: ileus, colitis, impaired gastric emptying, esophagitis, dysphagia, gastritis, gastrointestinal hemorrhage Hepatobiliary Disorders: acute hepatic failure, jaundice Skin and Subcutaneous Tissue Disorders: erythema multiforme Musculoskeletal, Connective Tissue, and Bone Disorders: muscular weakness, muscle spasms, trismus Renal and Urinary Disorders: nephrolithiasis, renal failure General Disorders and Administration Site Conditions: chills Investigations: increased transaminases, increased blood alkaline phosphatase, increased gamma-glutamyltransferase
Postmarketing Experience
The following adverse reaction has been identified during postapproval use of IXEMPRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Procedural Complications: Radiation recall
Warnings & Cautions for Ixempra
Myelosuppression Severe, life-threatening, or fatal myelosuppression can occur in patients treated with
IXEMPRA. Myelosuppression is dose-dependent and primarily manifests as neutropenia. In clinical studies, grade 4 neutropenia (<500 cells/mm 3 ) occurred in 36% of patients treated with IXEMPRA in combination with capecitabine and 23% of patients treated with single agent IXEMPRA monotherapy. Febrile neutropenia and infection with neutropenia were reported in 5% and 6% of patients treated with IXEMPRA in combination with capecitabine, respectively, and 3% and 5% of patients treated with IXEMPRA as a single agent, respectively.
Neutropenia-related death occurred in 1.9% of 414 patients with normal hepatic function or mild hepatic impairment treated with IXEMPRA in combination with capecitabine. The rate of neutropenia-related deaths was higher (29%, 5 out of 17) in patients with AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN . Neutropenia-related death occurred in 0.4% of 240 patients treated with IXEMPRA as a single agent. No neutropenia-related deaths were reported in 24 patients with AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN treated with IXEMPRA as a single agent.
IXEMPRA is contraindicated for use in patients with a neutrophil count of <1500 cells/mm 3. . Monitor patients receiving IXEMPRA for myelosuppression with frequent peripheral blood cell counts. Withhold, reduce, or discontinue IXEMPRA depending on the severity and persistence of myelosuppression .
Peripheral Neuropathy Peripheral neuropathy (sensory and motor neuropathy) occurred in patients treated
with IXEMPRA in combination with capecitabine and in patients treated with single agent IXEMPRA as shown in Table (see Table 3 ). Table 3: Peripheral Neuropathy a Sensory and motor neuropathy combined. b 24% and 27% of patients in 046 and 081, respectively, had preexisting neuropathy (grade 1). IXEMPRA IXEMPRA as with capecitabine Single Agent Study 046 Study 081 Peripheral neuropathy (all grades) a,b 67% 63% Peripheral neuropathy (grades 3/4) a,b 23% 14% Discontinuation due to neuropathy 21% 6% Median number of cycles to onset of grade 3/4 neuropathy 4 4 Median time to improvement of grade 3/4 neuropathy to baseline or to grade 1 6.0 weeks 4.6 weeks In Studies 046 and 081, 80% and 87%, respectively, of patients with peripheral neuropathy who received IXEMPRA had improvement or no worsening of their neuropathy following dose reduction. For patients with grade 3 or 4 neuropathy in Studies 046 and 081, 76% and 79%, respectively, had documented improvement to baseline or grade 1, twelve weeks after onset. A pooled analysis of 1540 cancer patients treated with IXEMPRA indicated that patients with diabetes mellitus or preexisting peripheral neuropathy may be at increased risk of severe neuropathy.
Patients with moderate to severe neuropathy (grade 2 or greater) were excluded from studies with IXEMPRA. Monitor patients for symptoms of neuropathy, such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, or neuropathic pain. Withhold, reduce, or discontinue IXEMPRA depending on the severity and persistence of peripheral neuropathy.
Increased Toxicities in Patients with Hepatic Impairment Patients with baseline
AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN experienced greater toxicity than patients with baseline AST or ALT ≤2.5 x ULN or bilirubin ≤1.5 x ULN when treated with IXEMPRA at 40 mg/m 2 in combination with capecitabine or as single agent in breast cancer studies. In combination with capecitabine, the overall frequency of grade 3/4 adverse reactions, febrile neutropenia, serious adverse reactions, and toxicity-related deaths was increased oin patients with hepatic impairment. IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to increased risk of toxicity- and neutropenia-related death.
With IXEMPRA single agent therapy, grade 4 neutropenia, febrile neutropenia, and serious adverse reatcitons were increased in patients with hepatic impairment
Hypersensitivity Reactions
IXEMPRA is contraindicated in patients with a history of a severe hypersensitivity reaction to agents containing Cremophor ® EL or its derivatives (eg, polyoxyethylated castor oil) . Of the 1323 patients treated with IXEMPRA in clinical studies, 9 patients (1 %) had experienced severe hypersensitivity reactions (including anaphylaxis). Three of the 9 patients were able to be retreated. Patients who experience a hypersensitivity reaction in one cycle of IXEMPRA must be premedicated in subsequent cycles with a corticosteroid in addition to the H 1 and H 2 antagonists, and extension of the infusion time should be considered Administer an H 1 and H 2 antagonist approximately 1 hour before IXEMPRA infusion and observe patients for hypersensitivity reaction occur, stop the infusion of IXEMPRA provide supportive treatment as clinically indicated (e.g.. epinephrine, corticosteriods).
Cardiac Adverse Reactions Cardiac adverse reactions (myocardial ischemia and ventricular dysfunction) occurred
in patients receiving IXEMPRA in combination with capecitabine (1.9%) and as a single agent (0.3%). Supraventricular arrhythmias were observed in the combination arm (0.5%). Closely monitor patients with a history of cardiac disease during treatment with IXEMPRA. Consider discontinuation of IXEMPRA in patients who develop cardiac ischemia or impaired cardiac function.
Embryo-Fetal Toxicity
Based on findings in animals and its mechanism of action, IXEMPRA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, intravenous administration of ixabepilone to pregnant rats and rabbits during the period of organogenesis caused maternal toxicity, embryo-fetal lethality, and fetal abnormalities at maternal exposures below the human clinical exposure based on AUC. Advise females of reproductive potential and pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IXEMPRA and for 7 months after the last dose.
Advise male patients with female partners of reproductive potential to use effective contraception during treatment with IXEMPRA and for 4 months after the last dose.
Alcohol Content
The alcohol content in a dose of IXEMPRA may affect the central nervous system and should be taken into account for patients in whom alcohol intake should be avoided or minimized. Consideration should be given to the alcohol content in IXEMPRA on the ability to drive or use machines immediately after the infusion. Each administration of IXEMPRA at the recommended dosage of 40 mg/m 2 delivers approximately 8.4 g/m 2 of ethanol.
For a patient with a BSA of 2.0 m 2, this would deliver approximately 16.8 grams of ethanol.
Drug Interactions with Ixempra
Effect of Other Drugs on
IXEMPRA Strong CYP3A4 Inhibitors The coadministration of IXEMPRA with a strong CYP3A4 inhibitor increased ixabepilone plasma concentration, which may increase the incidence and severity of adverse reactions of IXEMPRA. Avoid coadministration of IXEMPRA with strong CYP3A4 inhibitors. If the coadministration of IXEMPRA with strong CYP3A4 cannot be avoided, reduce the dose of IXEMPRA. Moderate or Weak CYP3A4 Inhibitors The coadministration of IXEMPRA with moderate or weak CYP3A4 inhibitors may increase the incidence and severity of adverse reactions of IXEMPRA. Monitor for adverse reactions and reduce the dose of IXEMPRA as recommended. Strong CYP3A4 Inducers The coadministration of IXEMPRA with a strong CYP3A4 inducer, decreased plasma concentrations of ixabepilone, which may decrease the efficacy of IXEMPRA. Avoid the coadministration IXEMPRA with strong CYP3A4 inducers.
If the coadministration of IXEMPRA with a strong CYP3A4 inducer cannot be avoided, increase the dose of IXEMPRA. Concomitant Use of IXEMPRA and Capecitabine No clinically meaningful differences in the pharmacokinetics of ixabepilone and capecitabine were observed when IXEMPRA was administered in combination with capecitabine (1000 mg/m 2 ).
Effect of Ixabepilone on Other Drugs Ixabepilone does not inhibit
CYP enzymes at relevant clinical concentrations and is not expected to alter the plasma concentrations of other drugs.
Capecitabine
In patients with cancer who received ixabepilone (40 mg/m 2 ) in combination with capecitabine (1000 mg/m 2 ), ixabepilone Cmax decreased by 19%, capecitabine Cmax decreased by 27%, and 5-fluorouracil AUC increased by 14%, as compared to ixabepilone or capecitabine administered separately. The interaction is not clinically significant given that the combination treatment is supported by efficacy data.
Pregnancy Safety for Ixempra
Pregnancy Risk Summary Based on findings in animals and its mechanism of action, IXEMPRA can cause fetal harm when administered to a pregnant woman . There are no available data on the use of IXEMPRA in pregnant women to inform the drug-associated risk. IXEMPRA contains alcohol which can interfere with neurobehavioral development. In animal reproduction studies, intravenous administration of ixabepilone to pregnant rats and rabbits during the period of organogenesis caused maternal toxicity, embryo-fetal lethality, and fetal abnormalities at maternal exposures below the human clinical exposure based on AUC (see Data). Advise females of reproductive potential and pregnant women of the potential risk to a fetus.
The background risk of major birth defects and miscarriage for the indicated population is unknown. 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. Clinical Considerations IXEMPRA contains alcohol . Published studies have demonstrated that alcohol is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development.
Data Animal data In embryo-fetal development studies, pregnant rats and rabbits received intravenous doses of 0.02, 0.08, and 0.3 mg/kg/day and 0.01, 0.03, 0.11, and 0.3 mg/kg/day, respectively during the period of organogenesis. In rats, an increase in resorptions and post-implantation loss and a decrease in the number of live fetuses and fetal weight was observed at the maternally toxic dose of 0.3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC). Abnormalities included a reduced ossification of caudal vertebrae, sternebrae, and metacarpals. In rabbits, ixabepilone caused maternal toxicity (death) and embryo-fetal toxicity (resorptions) at 0.3 mg/kg/day (approximately 0.1 times the human clinical dose based on body surface area).
Pediatric Use of Ixempra
Pediatric Use The alcohol content of IXEMPRA should be taken into account when given to pediatric patients . The safety and effectiveness of IXEMPRA in pediatric patients have not been established. Safety and efficacy were assessed, but not established for IXEMPRA across two studies: an open-label, dose-finding trial in 21 patients aged 2 to 18 years with advanced or refractory solid tumors and hematologic malignancies and a trial with 28 patients aged 3 to 18 years with advanced or refractory solid tumors that was terminated early due to lack of efficacy. No new safety signals were identified.
The median BSA normalized clearance of ixabepilone in 16 patients aged 2 to 18 years (17 L/h/m 2 ) was within range of that of patients greater than 18 years (20 L/h/m 2 ).
Contraindications for Ixempra
is contraindicated in patients who have: a neutrophil count <1500 cells/mm 3 or a platelet count <100,000 cells/mm 3. a history of severe hypersensitivity to agents containing Cremophor ® EL or its derivatives (e.g., polyoxyethylated castor oil). IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN. Baseline neutrophil count <1500 cells/mm 3 or a platelet count <100,000 cells/mm 3. Hypersensitivity to drugs formulated with Cremophor ® EL. IXEMPRA in combination with capecitabine is contraindicated for use in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN..
Overdosage Information for Ixempra
In patients who received an overdosage of IXEMPRA of up to 100 mg/m 2 (approximately 2.5 times the recommended dosage), peripheral neuropathy, fatigue, musculoskeletal pain/myalgia, and gastrointestinal symptoms (nausea, anorexia, diarrhea, abdominal pain, stomatitis) occurred. There is no known antidote for overdosage of IXEMPRA. In case of overdosage, closely monitor patients for adverse reactions and provide supportive treatment as clinically indicated.
Clinical Studies of Ixempra
Combination Therapy In an open-label, multicenter, multinational, randomized trial of 752 patients with metastatic or locally advanced breast cancer, the efficacy and safety of IXEMPRA (40 mg/m 2 every 3 weeks) in combination with capecitabine (at 1000 mg/m 2 twice daily for 2 weeks followed by 1 week rest) were assessed in comparison with capecitabine as a single agent (at 1250 mg/m 2 twice daily for 2 weeks followed by 1 week rest). Patients were previously treated with anthracyclines and taxanes. Patients were required to have demonstrated tumor progression or resistance to taxanes and anthracyclines as follows: tumor progression within 3 months of the last anthracycline dose in the metastatic setting or recurrence within 6 months in the adjuvant or neoadjuvant setting, and tumor progression within 4 months of the last taxane dose in the metastatic setting or recurrence within 12 months in the adjuvant or neoadjuvant setting. For anthracyclines, patients who received a minimum cumulative dose of 240 mg/m 2 of doxorubicin or 360 mg/m 2 of epirubicin were also eligible.
In this study, the median age of patients was 53 years, 67% were White, 23% were Asian, and 3% were Black; Karnofsky performance status was 70-100%, and 75% had received prior adjuvant or neo-adjuvant chemotherapy. Tumors were ER-positive in 47% of patients, ER-negative in 43%, HER2-positive in 15%, HER2-negative in 61%, and ER-negative, PR-negative, HER2-negative in 25%. The baseline disease characteristics and previous therapies for all patients (n=752) are shown in Table 6. Table 6: Baseline Disease Characteristics and Previous Therapies a For IXEMPRA plus capecitabine versus capecitabine only, prior treatment in the metastatic setting included cyclophosphamide (25% vs. 23%), fluorouracil (22% vs. 16%), vinorelbine (11% vs. 12%), gemcitabine (9% each arm), carboplatin (9% vs. 7%), liposomal doxorubicin (3% each arm), and cisplatin (2% vs. 3%). b Tumor progression within 3 months in the metastatic setting or recurrence within 6 months in the adjuvant or neoadjuvant setting. c 24% and 21% of patients had received 2 or more taxane-containing regimens in the combination and single agent treatment groups, respectively. IXEMPRA with capecitabine n=375 Capecitabine n=377 Site of disease Visceral disease (liver or lung) 316(84%) 315 (84%) Liver 245 (65%) 228(61%) Lung 180(48%) 174 (46%) Lymph node 250 (67%) 249 (66%) Bone 168(45%) 162 (43%) Skin/soft tissue 60(16%) 62(16%) Number of prior chemotherapy regimens in metastatic setting a 0 27 ( 7%) 33 ( 9%) 1 179(48%) 184(49%) 2 152(41%) 138(37%) ≥3 17 ( 5%) 22 ( 6%) Anthracycline resistance b 164(44%) 165 (44%) Taxane Resistance c Neoadjuvant/adjuvant setting 40(11%) 44(12%) Metastatic setting 327 (87%) 319 (85%) The patients in the combination treatment group received a median of 5 cycles of treatment and patients in the capecitabine single-agent treatment group received a median of 4 cycles of treatment.
The major efficacy outcome measures of the study was progression-free survival (PFS) defined as time from randomization to radiologic progression as determined by Independent Radiologic Review (IRR), clinical progression of measurable skin lesions or death from any cause. Additional efficacy outcome measures included objective tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST), response duration, and overall survival. IXEMPRA in combination with capecitabine resulted in a statistically significant improvement in PFS compared to capecitabine.
The results of the study are presented in Table 7 and Figure 1. Table 7: Efficacy of IXEMPRA in Combination with Capecitabine vs Capecitabine Alone - Intent-to-Treat Analysis a Stratified by visceral metastasis in liver/lung, prior chemotherapy in metastatic setting, and anthracycline resistance. b Cochran-Mantel-Haenszel test Efficacy Parameter IXEMPRA with capecitabine n=375 Capecitabine n=377 PFS Number of events 242 256 Median 5.7 months 4.1 months (95% Cl) (4.8 - 6.7) (3.1 - 4.3) Hazard Ratio (95% Cl) 0.69 (0.58 - 0.83) p-value a (Log rank) <0.0001 Objective Tumor Response Rate 34.7% 14.3% (95% Cl) (29.9 - 39.7) (10.9 -18.3) p-value a,b (CMH) <0.0001 Duration of Response, Median 6.4 months 5.6 months (95% Cl) (5.6 - 7.1) (4.2 - 7.5) Figure 1: Progression-free Survival Kaplan Meier Curves There was no statistically significant difference in overall survival between treatment arms in this study, as well as in a second similar study. In the study described above, the median overall survivals were 12.9 months (95% Cl: 11.5, 14.2) in the combination therapy arm and 11.1 months (95% Cl: 10.0,12.5) in the capecitabine alone arm [Hazard Ratio 90 (95% Cl: 0.77,1.05), p-value=0.19j. In the second trial, comparing IXEMPRA in combination with capecitabine versus capecitabine alone, conducted in 1221 patients pretreated with an anthracycline and a taxane, the median overall survival was 16.4 months (95% Cl: 15.0,17.9) in the combination therapy arm and 15.6 months (95% Cl: 13.9,17.0), in the capecitabine alone arm [Hazard Ratio 0.90 (95% Cl: 0.78,1.03), p-value=0.12. Figure 1 IXEMPRA as a Single Agent IXEMPRA was evaluated as a single agent in a multicenter single-arm study in 126 women with metastatic or locally advanced breast cancer.
The study enrolled patients whose tumors had recurred or had progressed following two or more chemotherapy regimens including an anthracycline, a taxane, and capecitabine. Patients who had received a minimum cumulative dose of 240 mg/m 2 of doxorubicin or 360 mg/m 2 of epirubicin were also eligible. Tumor progression or recurrence were prospectively defined as follows: Disease progression while on therapy in the metastatic setting (defined as progression while on treatment or within 8 weeks of last dose), Recurrence within 6 months of the last dose in the adjuvant or neoadjuvant setting (only for anthracycline and taxane), HER2-positive patients must also have progressed during or after discontinuation of trastuzumab.
In this study, the median age was 51 years (range, 30-78), and 79% were White, 5% Black, and 2% Asian, Kamofsky performance status was 70-100%, 88% had received two or more prior chemotherapy regimens for metastatic disease, and 86% had liver and/or lung metastases. Tumors were ER-positive in 48% of patients, ER-negative in 44%, HER2-positive in 7%, HER2-negative in 72%, and ER-negative, PR-negative, HER2-negative in 33%. IXEMPRA was administered at a dose of 40 mg/m 2 intravenously over 3 hours every 3 weeks. Patients received a median of 4 cycles (range 1 to 18) of IXEMPRA therapy.
Objective tumor response was determined by independent radiologic and investigator review using RECIST. Efficacy results are presented in Table 8. Table 8: Efficacy of IXEMPRA in Metastatic and Locally Advanced Breast Cancer a All responses were partial. b As assessed by IRR. Endpoint Result Objective tumor response rate (95% Cl) IRR Assessment a (n=113) Investigator Assessment (n=126) 12.4% (6.9 -19.9) 18.3% (11.9-26.1) Time to response b (n=14) Median, weeks (min - max) 6.1 (5 - 54.4) Duration of response b (n=14) Median, months (95% Cl) 6.0 (5.0 - 7.6)
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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