Ixabepilone (Ixempra)

Number: 0869

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

---

Policy

1. Criteria for Initial Approval

   Breast cancer

   Aetna considers ixabepilone (Ixempra) medically necessary for treatment of breast cancer when any of the following criteria are met:

   1. Member has human epidermal growth factor receptor 2 (HER2)-negative locally advanced, recurrent or metastatic disease or disease with no response to preoperative systemic therapy, as a single agent; or
   2. Member has human epidermal growth factor receptor 2 (HER2)-positive recurrent or metastatic disease or disease with no response to preoperative systemic therapy, in combination with trastuzumab; or
   3. The requested medication will be used in combination with capecitabine for treatment of metastatic or locally advanced disease when the following criteria are met:
      
      
      1. Member has failed an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated; and
      2. Member does not have aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level greater than 2.5 times the upper limit of normal (ULN) or bilirubin greater than 1 time the ULN.

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

2. Continuation of Therapy

   Aetna considers continuation of ixabepilone (Ixempra) therapy medically necessary in members with an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

Ixabepilone is available as Ixempra for injection in 15 mg and 45 mg vials.

Breast cancer: The recommended dosing regimen for Ixempra (ixabepilone) consists of: 40 mg/m² IV over three hours every three weeks; use MAX body surface area (BSA) of 2.2 m² (88 mg) in members whose BSA is greater than 2.2 m².

Premedicate one hour before each infusion with an H1 antagonist and an H2 antagonist; additionally premedicate with a corticosteroid in persons with a previous hypersensitivity reaction.

The maximum dose of ixabepilone per treatment is 88mg.

Continued use beyond 3 months (12 weeks) is considered medically necessary for persons with stable disease (tumor size within 25 % of baseline).  Continued use is considered not medically necessary when there is evidence of disease progression or unacceptable toxicity occurs.

Refer to full prescribing information for Ixempra for preparation and administration instructions and dosage modifications.

Source: R-Pharm US, 2016

Experimental and Investigational or Not Medically Necessary

Aetna considers ixabepilone (Ixempra) not medically necessary for members that have experienced severe (CTC grade 3/4) hypersensitivity reaction to medications formulated with Cremophor EL or its derivatives (e.g., polyoxyethylated castor oil).

Aetna considers ixabepilone (Ixempra) experimental and investigational for all other indications including the following (not an all-inclusive list):

• Cervical cancer
• Colorectal cancer
• Endometrial cancer
• Fallopian tube cancer
• Gastric cancer
• Medulloblastoma
• Meningioma
• Non-small-cell lung cancer
• Osteosarcoma
• Ovarian cancer
• Pancreatic cancer
• Primary peritoneal cancer
• Prostate cancer
• Renal cell carcinoma
• Triple-negative breast cancer
• Uterine cancer/uterine leiomyosarcoma/carcinosarcoma of the uterus.

---

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
84450	Transferase; aspartate amino (AST) (SGOT)
84460	Transferase; alanine amino (ALT) (SGPT)
96413	Chemotherapy administration, intravenous infusion technique; up to 1 hour, single or initial substance/drug
+96415	each additional hour (List separately in addition to code for primary)
HCPCS codes covered if selection criteria are met:
J9207	Injection, ixabepilone, 1 mg
Other HCPCS codes related to the CPB:
J8520	Capecitabine, oral, 150 mg
J8521	Capecitabine, oral, 500 mg
J9171	Injection, docetaxel, 1 mg
J9172	Injection, docetaxel (ingenus) not therapeutically equivalent to j9171, 1 mg
J9258	Injection, paclitaxel protein-bound particles (teva) not therapeutically equivalent to j9264, 1 mg
J9259	Injection, paclitaxel protein-bound particles (american regent) not therapeutically equivalent to j9264, 1 mg
J9264	Injection, paclitaxel protein-bound particles, 1 mg
J9267	Injection, paclitaxel, 1 mg
J9355	Trastuzumab, 10 mg
ICD-10 codes covered if selection criteria are met :
C50.011 - C50.929	Malignant neoplasm of breast
ICD-10 codes not covered for indications listed in the CPB (not all inclusive):
C16.0 - C16.9	Malignant neoplasm of stomach
C18.0 - C18.9	Malignant neoplasm of colon
C25.0 - C25.9	Malignant neoplasm of pancreas
C34.00 - C34.92	Malignant neoplasm of bronchus and lung [non small-cell]
C40.00 - C41.9	Malignant neoplasm of bone and articular cartilage [osteosarcoma]
C53.0 - C55	Malignant neoplasm of uterus [uterine leiomyosarcoma]
C56.1 - C56.9	Malignant neoplasm of ovary
C61	Malignant neoplasm of prostate
C64.1 - C65.9	Malignant neoplasm of kidney and renal pelvis
C70.0	Malignant neoplasm of cerebral meninges
C71.6	Malignant neoplasm of cerebellum [Medulloblastoma]
Z88.8	Allergy status to other drugs, medicaments and biological substances status [severe (CTC grade 3/4) hypersensitivity reaction to medications formulated with Cremophor EL or its derivatives]

---

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• In combination with capecitabine for the treatment of 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
• Monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine

Compendial Uses

• Breast cancer

Ixabepilone (Ixempra), an epothilone B analog, is an antimicrotubule agent. Ixempra (ixabepilone) inhibits microtubles, halting cell division in the mitotic phase and resulting in subsequent cell death. Ixempra (ixabepilone) stabilizes the microtubules by directly binding to the beta‐tubulin subunits (alpha‐beta‐II and alpha‐beta‐III). Epothilones are isolated from the myxobacterium, Sorangium cellulosum.

Ixabepilone was approved by the Food and Drug Administration (FDA) 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.  The FDA labeling indicates Ixabepilone as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine.

Black Box Warning: Toxicity in Hepatic Impairment - Ixempra (ixabepilone) in combination with capecitabine is contraindicated in patients with AST or ALT greater than 2.5 times the upper limit of normal (ULN) or bilirubin greater than 1 times the ULN due to increased risk of toxicity and neutropenia‐related death. Please refer to current prescribing information for dose adjustments.

Per the prescribing information, Ixempra carries the following contraindications:

• Hypersensitivity to drugs formulated with Cremophor EL
• Baseline neutrophil count <1500 cells/mm3 or a platelet count <100,000 cells/mm3
• Patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN must not be treated with Ixempra (ixabepilone) in combination with capecitabine.

According to the prescribing information, Ixempra carries the following warnings and precautions:

• Peripheral neuropathy: Monitor for symptoms of neuropathy, primarily sensory. Neuropathy is cumulative, generally reversible, and should be managed by dose adjustment and delays.
• Myelosuppression: Primarily neutropenia. Monitor with peripheral blood cell counts and adjust dose as appropriate.
• Hypersensitivity reaction: Must premedicate all patients with an H1 antagonist and an H2 antagonist before treatment.
• Fetal harm can occur when administered to a pregnant woman. Women should be advised not to become pregnant when taking Ixempra.

The most common adverse reactions (≥20%), per the prescribing information, include: peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain. Additional reactions occurred in ≥20% in combination treatment: palmar-plantar erythrodysesthesia syndrome, anorexia, abdominal pain, nail disorder, and constipation.

Drug-associated hematologic abnormalities (>40%), per the prescribing information, include neutropenia, leukopenia, anemia, and thrombocytopenia 

Refer to the full prescribing information for Ixempra for drug interactions and use in specific populations.

In a phase II study, Kim et al (2012) examined the effects of ixabepilone in patients with advanced gastric cancer previously treated with fluoropyrimidine-based chemotherapy.  Asian patients with unresectable or metastatic gastric adenocarcinoma who had failed fluoropyrimidine-based chemotherapy received ixabepilone 40 mg/m(2) by 3-hour intravenous infusion every 3 weeks.  The primary end-point was objective response rate (ORR).  A total of 52 patients were treated (65.4 % men; median age of 56.5 years).  The ORR was 15.4 % (95 % confidence interval [CI]: 6.9 to 28.1); 8 patients achieved partial responses (PR) for a median duration of 3.1 months (95 % CI: 2.6 to 4.1 months) and 26 patients (50.0 %) had stable disease SD).  Median progression-free survival (PFS) was 2.8 months (95 % CI: 2.1 to 3.5 months).  The most common grade 3 non-hematological toxicities were fatigue (9.6 %), decreased appetite (7.7 %), sensory neuropathy (5.8 %), and diarrhea (5.8 %).  Grade 3/4 neutropenia occurred in 46.2 % of patients.  The authors concluded that ixabepilone is active in Asian patients with advanced gastric cancer and shows a toxicity profile similar to those previously reported in other tumor types.  These findings need to be validated in phase III clinical trials.

Vishnu et al (2012) evaluated anti-tumor activity of the combination of ixabepilone and sunitinib in pre-clinical models of chemotherapy naïve and refractory epithelial ovarian tumors, and investigated the mechanism of synergy of such drug combination.   HOVTAX2 cell line was derived from a metastatic serous papillary epithelial ovarian tumor (EOC) and a paclitaxel-resistant derivative was established.  Dose response curves for ixabepilone and sunitinib were generated and synergy was determined using combination indexes.  The molecular mechanism of anti-tumor synergy was examined using shRNA silencing.  The combination of ixabepilone and sunitinib demonstrated robust anti-tumor synergy in naive and paclitaxel-resistant HOVTAX2 cell lines due to increased apoptosis.  The GTPase, RhoB, was synergistically up-regulated in cells treated with ixabepilone and sunitinib.  Using shRNA, RhoB was demonstrated to mediate anti-tumor synergy.  These results were validated in 2 other EOC cell lines.  The authors concluded that ixabepilone plus sunitinib demonstrated anti-tumor synergy via RhoB in naive and paclitaxel-resistant cells resulting in apoptosis.  This study demonstrated a novel mechanism of action leading to anti-tumor synergy and provided “proof-of-principle” for combining molecular targeted agents with cytotoxic chemotherapy to improve anti-tumor efficacy.  They stated that RhoB could be envisioned as an early biomarker of response to therapy in a planned phase II clinical trial to assess the efficacy of ixabepilone combined with a receptor tyrosine kinase inhibitor such as sunitinib.  To the best of the authors’ knowledge, this was the first demonstration of anti-tumor synergy between these 2 classes of drugs in EOC and the pivotal role of RhoB in this synergy.

In a phase II clinical trial, Liu et al (2012) evaluated the activity of a weekly ixabepilone in men with metastatic castrate-resistant prostate cancer (CRPC) to minimize hematologic toxicity.  These investigators reported the activity and toxicity of ixabepilone, administered by using a weekly schedule, in men with metastatic CRPC.  Patients with metastatic CRPC received ixabepilone at 20 mg/m(2) intravenous weekly x 3, in 4-week cycles.  This non-comparative study stratified patients to either a chemotherapy naive (CN), prior taxane (Tax) only, or 2 prior cytotoxic (TCx) chemotherapy arm.  The primary end-point was prostate-specific antigen response by using PCWG (Prostate Cancer Working Group) 1 criteria.  Secondary end-points included radiographic response when using RECIST (Response Evaluation Criteria In Solid Tumors).  A total of 124 patients were enrolled, of whom, 109 were eligible (35 CN, 42 Tax, and 32 TCx) for the primary response determination in this study.  Prostate-specific antigen responses were seen in 12 (34.3 %) of 35, 12 (28.6 %) of 42, and 7 (21.9 %) of 32 patients with the partial objective response in 5 (22.7 %) of 22, 2 (8.0 %) of 25, and 0 (0.0 %) of 24 patients for the CN, Tax, and TCx arms, respectively.  Significant (grade 3/4) neutropenia was seen in 6 (15.4 %), 7 (14.6 %), and 9 (25.0 %); and grade 3/4 sensory neuropathy was seen in 8 (20.5 %), 12 (25.0 %), and 12 (33.3 %) for CN, Tax, and TCx, respectively.  Grade 3/4 thrombocytopenia was infrequent and seen in only 1 patient on the CN and the TCx arm.  The authors concluded that ixabepilone was found to have an acceptable toxicity profile when administered by using a weekly schedule with less myelosuppression compared with prior studies when using the every 3-week schedule.  Single-agent activity was observed and met pre-specified activity levels for the Tax-treated arm.  These findings need to be validated in phase III clinical trials.

In a phase II clinical trial, Edelman et al (2013) evaluated ixabepilone-based chemotherapy in stage IIIb/IV non-small-cell lung cancer (NSCLC), compared with paclitaxel-based chemotherapy.  Tumor specimens were prospectively evaluated for β3T expression.  Patients were stratified by β3T status (positive versus negative) and randomly assigned at a ratio of 1:1 to receive ixabepilone (32 mg/m(2)) and carboplatin (area under concentration-time curve [AUC], 6) or paclitaxel (200 mg/m(2)) and carboplatin (AUC, 6) for up to 6 cycles.  The primary end-point was PFS in the β3T-positive subgroup.  A total of 95 patients (β3T positive, 52; β3T negative, 43) received ixabepilone plus carboplatin; 96 patients (β3T positive, 49; β3T negative, 47) received paclitaxel plus carboplatin.  No significant differences in median PFS were observed between arms for either subgroup (β3T positive, 4.3 months in both arms; β3T negative, 5.8 versus 5.3 months).  Ixabepilone did not significantly improve overall survival (OS) for the β3T-positive subset or the overall population.  Adverse events were similar between the 2 arms and comparable with those in previous studies.  The authors concluded that there was no predictive value of β3T in differentiating clinical activity of ixabepilone- or paclitaxel-containing regimens.  Ixabepilone did not improve PFS or OS in patients with β3T-positive tumors.  β3T-positive patients had worse PFS relative to β3T-negative patients, regardless of treatment; hence, β3T expression seems to be a negative prognostic factor, but not a predictive factor, in advanced NSCLC treated with either ixabepilone or paclitaxel platinum-based doublets.

von Roemeling et al (2013) noted that metastatic renal cell carcinoma (mRCC) is more resistant to conventional cytotoxic chemotherapeutic agents than other solid tumors.  Although significant progress has been made over the last decade with several novel therapeutics, these agents invariably go on to fail, largely due to either intrinsic or acquired resistance.  To help overcome, or at least delay resistance, combinatorial therapies utilizing agents with disparate, and ideally complementary, mechanisms of actions are needed.  In this report, these researchers assessed the novel combination of the mTOR inhibitor, temsirolimus, with ixabepilone in RCC.  The authors concluded that the results demonstrated synergy in multiple cell lines of RCC and further evaluation of this combination is warranted in the clinical setting.

Smaglo et al (2014) stated that the management of metastatic pancreatic adenocarcinoma is a challenge for medical oncologists because of both the aggressive nature of the disease and the relative paucity of effective systemic treatments with activity against this type of tumor.  In the effort to discover new agents and combinations that may augment the therapeutic arsenal available for the management of this cancer, early phase clinical trials have been performed using ixabepilone with promising results.  Targeting the microtubule system with certain taxanes in the management of pancreatic adenocarcinoma has been validated; ixabepilone also targets the microtubule system, interfering with it in an alternate manner from the taxane mechanism.  Ixabepilone has demonstrated activity in cancers that have become taxane-resistant as well as those that never had any demonstrable taxane susceptibility.  The available data for the use of ixabepilone in the management of pancreatic adenocarcinoma are limited but promising.  Single-arm studies have demonstrated both clinical efficacy and tolerable toxicity for the use of ixabepilone as monotherapy.  The trial data available for ixabepilone used as a part of combination therapy are similar: it has been paired with chemotherapy (carboplatin, irinotecan) and biologic therapy (dasatinib, sunitinib) at the phase I level to treat solid tumors in general, again with tolerable side effects and a suggestion of benefit.  A single phase II study has evaluated combination therapy with ixabepilone in the management of patients with pancreatic cancer, pairing it with cetuximab with clinical benefit.  The authors concluded that although these trials are promising with regard to addition of ixabepilone to the slim armamentarium for management of pancreatic cancer, further work still needs to be done.  

Yadav et al (2014) noted that triple-negative breast cancer (TNBC) is defined by the lack of immunohistochemical expression of the estrogen and progesterone receptors and human epidermal growth factor receptor 2 (EGFR2).  Most TNBC has a basal-like molecular phenotype by gene expression profiling and shares clinical and pathological features with hereditary BRCA1 related breast cancers.  These investigators evaluated the activity of available chemotherapy and targeted agents in TNBC.  A systematic review of PubMed and conference databases was carried out to identify randomized clinical trials (RCTs) reporting outcomes in women with TNBC treated with chemotherapy and targeted agents.  They identified TNBC studies of chemotherapy and targeted agents with different mechanisms of action, including induction of synthetic lethality and inhibition of angiogenesis, growth and survival pathways.  Triple-negative breast cancer is sensitive to taxanes and anthracyclines.  Platinum agents are effective in TNBC patients with BRCA1 mutation, either alone or in combination with poly adenosine diphosphate polymerase 1 inhibitors.  Combinations of ixabepilone and capecitabine have added to PFS without survival benefit in metastatic TNBC.  Anti-angiogenic agents, tyrosine kinase inhibitors and EGFR inhibitors in combination with chemotherapy produced only modest gains in PFS and had little impact on survival.  Triple-negative breast cancer subgroups responded differentially to specific targeted agents.  The authors concluded that in the future, the treatment needs to be tailored for a specific patient, depending on the molecular characteristics of their malignancy.  Moreover, they noted that TNBC, being a chemosensitive entity, combination with targeted agents have not produced substantial improvements in outcomes.  Appropriate patient selection with rationale combinations of targeted agents is needed for success.

Tredan et al (2015) stated that despite high initial sensitivity to chemotherapy, TNBC is associated with a poor prognosis, highlighting the need for novel therapeutic strategies.  In a multi-center, randomized, open-label phase II clinical trial, these researchers evaluated the effectiveness of ixabepilone as monotherapy, and the combination of ixabepilone with cetuximab, as first-line treatment in patients with triple-negative locally advanced non-resectable and/or metastatic breast cancer.  Women were randomly assigned to receive either ixabepilone (40 mg/m2) every 21 days (n = 40), or ixabepilone (40 mg/m2) every 21 days with cetuximab (400 mg/m2 loading dose, followed by 250 mg/m2) once-weekly (n = 39).  The primary end-point of the trial was to estimate the response rates of ixabepilone monotherapy and ixabepilone with cetuximab combination therapy.  Of 79 randomized patients, 77 were treated.  Based on an intent-to-treat analysis, an objective response rate of 30 % (95 % CI: 16.6 to 46.5) was observed in the monotherapy arm, and 35.9 % (95 % CI: 21.2 to 52.8) in the combination arm.  Median PFS was 4.1 months in both treatment groups.  Safety findings were consistent with the known individual toxicity profiles of ixabepilone and cetuximab.  Skin and subcutaneous tissue disorders were more common with combination therapy, as were discontinuations because of adverse events.  The authors concluded that ixabepilone monotherapy and the ixabepilone and cetuximab combination demonstrated similar levels of clinical activity in first-line treatment of advanced TNBC, with a predictable safety profile.  They stated that further investigation of novel therapies for TNBC is needed to improve patient outcomes.

In a phase II clinical trial, Duska et al (2014) determined the activity of ixabepilone as a single-agent as second-line treatment for patients with metastatic uterine leiomyosarcoma who had received taxane based therapy.  Eligible women with unresectable uterine leiomyosarcoma progressing after prior cytotoxic therapy containing a taxane were treated with ixabepilone 40 mg/m2 on day one of a 21-day cycle.  Patients with prior pelvic radiation were treated without dose reduction.  Response Evaluation Criteria in Solid Tumors response was assessed by computed tomography (CT).  Twenty-three of 26 women were evaluable (2 wrong histology, 1 never treated) with 2 of 23 receiving 1 cycle of therapy.  There were no complete responses (CR) or PR.  Stable disease was seen in 4 patients (17.4 %, median of 3.4months).  Seventeen patients (73.9 %) had increasing disease (PD) and 2 patients were inevaluable per RECIST.  One patient had SD over 6 cycles of treatment.  Median PFS for all 23 patients was 1.4 months and OS was 7.0 months.  The predominant grade 3 or 4 toxicity was uncomplicated myelosuppression: neutropenia grade 3 (13 %), grade 4 (17 %), and anemia grade 3 (22 %).  The authors concluded that ixabepilone as a single agent is not an active second-line therapy for uterine leiomyosarcoma previously treated with a taxane.

Cervical Cancer

Burotto et al (2015) stated that ixabepilone is a microtubule-stabilizing agent approved for metastatic breast cancer. Pre-clinical data have shown that ixabepilone is active in taxane-sensitive and -resistant cells. Metastatic cervical carcinoma (mCC) has a poor prognosis and no established second-line therapies. This study assessed the safety and effectiveness of ixabepilone in previously treated mCC. Patients with histologically confirmed mCC and at least 1 prior cisplatin-containing regimen were treated with ixabepilone [6 mg/m(2) per day for 5 days] every 21 days. The primary end-point was PFS according to RECIST. Secondary end-points were response rate, rate of tumor growth, OS, and safety. Levels of glu-terminated and acetylated tubulin, markers of microtubule stabilization, and surrogates for target engagement were assessed by Western blot. In total, 41 patients were enrolled; 34 had tumors with primarily squamous histology. The median number of prior therapies was 2 (range of 1 to 6). Four patients (9.7 %) had a PR. Median PFS in months was 2.3 for all, 3.84 for taxane-naïve, and 2.03 for taxane-pretreated patients (p = 0.13). Consistent with this, these researchers found statistically similar (p = 1) rates of growth in taxane-naive patients (0.0035 per day) and taxane pretreated patients (0.0053 per day). Median OS was 5.84 months. G1/2 toxicities included vomiting (43 %), sensory neuropathy (21 %), and fatigue (60 %). Bowel fistulas were observed in 7 % of patients. Glu and acetylated tubulin were assessed in tumor samples from 11 patients during the first cycle of treatment. Although there was clear evidence of "target engagement" and microtubule stabilization in all tumors, a correlation between the extent of tubulin stabilization and response to therapy could not be demonstrated. The authors concluded that ixabepilone was well-tolerated but showed very modest activity in second- or later-line mCC and cannot be recommended as a therapy. Target engagement was demonstrated but was not correlated with responses, suggesting that other factors mediate drug sensitivity. New strategies are needed for refractory mCC.   These investigators stated that accrual to cervical cancer studies remains a puzzling challenge given the lack of options and the dismal prognosis of this disease. The majority of patients referred for a trial such as this had very advanced disease that is difficult to manage. The observation of 4 PRs among the 41 patients indicated that ixabepilone has some activity but not sufficient for further development without greater understanding of mechanisms of sensitivity and resistance.

Colorectal Cancer

In a phase I clinical trial, Montero and colleagues (2016) evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics/pharmacodynamics, and early clinical activity of ixabepilone given either weekly or every 3 weeks in combination with daily sunitinib in patients with advanced solid tumors.  Eligible patients received either weekly (schedule A) or every 3 weeks (schedule B) ixabepilone at escalating doses (schedule A: 7.5, 15, or 20 mg/m(2); schedule B: 20, 30, or 40 mg/m(2)), and oral sunitinib (37.5 mg daily), starting on day 8 of cycle 1; dose-limiting toxicities (DLT) were assessed during cycle 1.  The ixabepilone and sunitinib combination was fairly well-tolerated; DLTs were observed in 3 subjects (1 in schedule 3A and 2 in schedule 3B).  The most common grade 3 to 4 hematologic and non-hematologic AEs were leukopenia and fatigue, respectively; 4 patients (3 in schedule A) achieved a PR, while 13 patients had SD; 9 of 17 heavily pre-treated colorectal cancer patients had clinical benefit.  Co-administration of sunitinib with ixabepilone on a weekly (but not every 3 week) schedule was associated with a significant increase in the half-life and a significant decrease in the clearance of ixabepilone.  Correlative studies demonstrated a significant association between higher baseline plasma angiogenic activity (PAA) and clinical benefit in schedule A patients.  Weekly, but not every 3 weeks, ixabepilone led to a significant decrease in PAA post-baseline.  The authors concluded that co-administration of ixabepilone with sunitinib had acceptable toxicity and encouraging clinical activity in heavily pre-treated patients, particularly in patients with metastatic colorectal cancer.  They stated that further confirmation of the clinical activity of this combination, especially in patients with advanced colorectal cancer, and validation of PAA as a potentially useful angiogenesis biomarker is needed.

Endometrial Cancer

In a multi-center, open label, randomized phase III clinical trial, McMeekin et al (2015) examined if ixabepilone resulted in improved OS compared with commonly used single-agent chemotherapy (doxorubicin or paclitaxel) in women with locally advanced, recurrent, or metastatic endometrial cancer with at least 1 failed prior platinum-based chemotherapeutic regimen. Patients were randomized 1:1 to ixabepilone (40 mg/m(2)), or either paclitaxel (175 mg/m(2)) or doxorubicin (60 mg/m(2)), every 21days. Patients that had previously received an anthracycline were randomized to ixabepilone or paclitaxel; all other patients were randomized to ixabepilone or doxorubicin. An interim analysis of futility for OS was planned. At the time of database lock, 496 patients were randomized to receive ixabepilone (n = 248) or control (n = 248); 9 patients in the control arm were not treated. The interim analysis of futility for OS (219 events) favored the control chemotherapy arm (hazard ratio [HR] = 1.3 [95 % CI: 1.0 to 1.7], stratified log rank test p = 0.0397), indicating that the study would not meet its primary objective. The study was discontinued based on the interim OS results. The frequency of adverse events was comparable between the treatment arms. The authors conclude that the findings of this study did not meet its primary objective of improving OS in the ixabepilone arm compared to the control chemotherapy arm. A favorable risk/benefit ratio was not observed for ixabepilone versus control at the time of the interim analysis. The safety results were consistent with the known safety profiles of ixabepilone and control.

Fallopian Tube and Primary Peritoneal Cancers

Zagouri et al (2015) noted that ovarian cancer is the most lethal gynecologic malignancy; consequently, there is a need for effective therapies. Epothilones are microtubule-stabilizing agents that inhibit cell growth. Currently, patupilone and its 4 synthetic derivatives ixabepilone, BMS-310705, sagopilone, 20-desmethyl-20-methylsulfanyl epothilone B and epothilone D, as well as its derivative KOS-1584, are under clinical evaluation. This was the first systematic review conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines that synthesized all available data emerging from trials and evaluates the safety and effectiveness of epothilones in epithelial ovarian, primary fallopian tube, and primary peritoneal cancer. Despite the fact that epothilones have proven active in taxane-resistant settings in pre-clinical models, it is not yet clear from phase II/III studies reviewed here that their clinical activity is superior to that of taxanes. Nevertheless, responses to epothilones have been observed in platinum-refractory/resistant ovarian cancer patients. Moreover, despite the shared mechanism of action of epothilones, their clinical profile seems clearly different, with diarrhea being the most common dose-limiting toxicity encountered with patupilone, whereas neutropenia and sensory neuropathy are the most common toxic effects observed with the other epothilones. The authors concluded that randomized trials comparing epothilones with standard treatments are needed to define further the role of these agents, whereas biomarker analysis might further optimize patient selection.

In a multi-center, phase-II clinical trial, Rogue et al (2022) examined activity/safety of ixabepilone + bevacizumab (IXA + BEV) compared to IXA alone in platinum-resistant/refractory ovarian/fallopian tube/primary peritoneal cancer. In addition, these investigators examined the role of prior BEV and taxanes; and examined class III-ß-tubulin (TUBB3) as a predictive biomarker. Subjects were randomized to receive IXA 20 mg/m2 days 1, 8, 15 with (IXA + BEV) or without (IXA) BEV 10 mg/kg days 1, 15 every 28 days. Patients were stratified by prior BEV. The primary endpoint was PFS; secondary endpoints were OS, safety, and ORR. Among 76 evaluable patients who received IXA + BEV (n = 39) compared to IXA alone (n = 37), the ORR was 33 % (n = 13) versus 8 % (n = 3)(p = 0.004), durable at 6 months in 37 % (n = 14) and 3 % (n = 1) (p < 0.001). BEV significantly improved PFS (median of 5.5 versus 2.2 months, HR = 0.33, 95 % CI: 0.19 to 0.55, p < 0.001) and OS (median of 10.0 versus 6.0 months, HR = 0.52, 95 % CI: 0.31 to 0.87, p = 0.006). Both regimens were well-tolerated; and TUBB3 expression did not predict response. Subgroup analyses revealed minimal effect of prior BEV or taxane resistant/refractory status on response to IXA + BEV. The authors concluded that IXA + BEV was a well-tolerated, effective combination for platinum/taxane-resistant ovarian cancer that extended PFS and likely OS relative to IXA monotherapy. Prior receipt of BEV should not preclude the use of IXA + BEV. TUBB3 is not a predictive biomarker.

Medulloblastoma

Genovesi and colleagues (2021) stated that medulloblastoma (MB) is the most common malignant pediatric brain tumor and a leading cause of cancer-related mortality and morbidity. Existing treatment protocols are aggressive in nature resulting in significant neurological, intellectual, and physical disabilities for the children undergoing treatment; therefore, there is an urgent need for improved, targeted therapies that minimize these harmful side effects. By means of a network-based systems pharmacogenomics approach, these researchers identified candidate drugs for MB. Based on results from a functional genomics screen, these investigators identified a network of interactions implicated in human MB growth regulation. These investigators then integrated drugs and their known mechanisms of action, along with gene expression data from a large collection of medulloblastoma patients to identify drugs with potential to treat MB. The analyses identified drugs targeting CDK4, CDK6 and AURKA as strong candidates for MB; all of these genes are well validated as drug targets in other tumor types. These researchers also identified non-WNT MB as a novel indication for drugs targeting TUBB, CAD, SNRPA, SLC1A5, PTPRS, P4HB and CHEK2. Based upon these analyses, they subsequently demonstrated that one of these drugs, the new microtubule stabilizing agent, ixabepilone, blocked tumor growth in-vivo in mice bearing patient-derived xenograft tumors of the Sonic Hedgehog and Group 3 subtype, providing the 1st demonstration of its effectiveness in MB. The authors concluded that these findings confirmed that this data-driven systems pharmacogenomics strategy is a powerful approach for the discovery and validation of novel therapeutic candidates relevant to MB treatment, and along with data validating ixabepilone in PDX models of the 2 most aggressive subtypes of medulloblastoma.

Meningioma

Jungwirth et al (2023) stated that currently there are no systemic therapeutic options for patients with recurrent or refractory meningioma. These researchers carried out a large-scale drug screening using FDA-approved drugs on several meningioma cell lines to identify effective drugs. The impact of the top 4 compounds was evaluated on cell viability, proliferation, colony formation, migration, and apoptosis. Furthermore, the anti-neoplastic effects of the selected drugs were validated in a heterotopic xenograft mouse model. Analyses of the viability of meningioma cells treated with 119 anti-neoplastic FDA-approved drugs resulted in categorization into sensitive and resistant drug-response groups based on the mean IC50 values and peak serum concentrations (Cmax) in patients. A total of 80 drugs, including 15 alkylating agents, 14 anti-metabolites, and 13 tyrosine kinase inhibitors (TKIs), were classified as resistant (IC50 > Cmax). The sensitive drug-response group (n = 29, IC50 < Cmax) included RNA/protein synthesis inhibitors, proteasome inhibitors, topoisomerase, tyrosine-kinase, and partial histone deacetylase and microtubule inhibitors. The IC50 of the 4 most effective compounds (carfilzomib, omacetaxine, ixabepilone, and romidepsin) ranged from 0.12 to 9.5 nM. Most of them caused cell cycle arrest in the G2/M-phase and induced apoptosis. Additionally, all drugs except romidepsin significantly inhibited tumor growth in-vivo. The strongest anti-neoplastic effect was observed for ixabepilone, which reduced tumor volume by 86 %. The authors concluded that a large-scale drug screening provided a comprehensive insight into the anti-meningioma activities of FDA-approved drugs, and identified carfilzomib, omacetaxine, ixabepilone, and romidepsin as novel potent anti-neoplastic agents for the treatment of aggressive meningiomas. The most pronounced effects were observed with ixabepilone mandating for further clinical investigation.

Osteosarcoma

Yu and co-workers (2015) noted that systemic therapy has improved osteosarcoma event-free survival (EFS) and OS, but 30 to 50 % of patients originally diagnosed will have progressive or recurrent disease, which is difficult to cure.  Osteosarcoma has a complex karyotype, with loss of p53 in the vast majority of cases and an absence of recurrent, targetable pathways.  These researchers examined 54 agents that are clinically approved for other oncologic indications, agents in active clinical development, and others with promising preclinical data in osteosarcoma at clinically achievable concentrations in 5 osteosarcoma cell lines. They found significant single-agent activity of multiple agents and tested 10 drugs in all permutations of 2-drug combinations to define synergistic combinations by Chou and Talalay analysis. These investigators then evaluated order of addition to choose the combinations that may be best to translate to the clinic.  The authors concluded that the re-purposing of chemotherapeutics in osteosarcoma by using an in-vitro system may define novel drug combinations with significant in vivo activity.  In particular, combinations of targeted, targeted and cytotoxic, or multiple cytotoxic agents can be explored with this methodology.  Particularly for diseases such as osteosarcoma that have few presently available treatments avenues, this important early pre-clinical data can serve as the basis for confirmatory assays, explorations into the mechanisms of the most promising agents, canine or xenograft studies, and ultimately clinical trials.

Renal Cell Carcinoma

In this single-arm, phase II clinical trial, Burotto and colleagues (2017) examined the effectiveness of a combination of ixabepilone plus bevacizumab in patients with refractory metastatic renal cell carcinoma (mRCC).  These researchers enrolled 30 patients with histologically confirmed mRCC, clear cell subtype, who had not been previously treated with ixabepilone or bevacizumab but had received at least 1 prior FDA-approved treatment for RCC.  The treatment regimen consisted of 6 mg/m2 ixabepilone per day for 5 days and 15 mg/kg bevacizumab every 21 days.  After 6 cycles, the treatment interval could be extended to every 28 days.  The primary end-point was the ORR according to the RECIST; secondary end-points were PFS, OS, and the toxicity of the combination.  The median number of prior therapies was 2 (range of 1 to 5).  Patients received a median of 8 cycles of ixabepilone plus bevacizumab (range of 2 to 54).  The median follow-up was 36.4 months (range of 23.5 to 96.5).  A total of 19 patients (63.3 %) had SD as a best response; 3 patients (10 %) had a PR.  The median PFS was 8.3 months (95 % CI: 4.9 to 10.6) and the median OS was 15.0 months (95 % CI: 11.3 to 28.8).  The total number of cycle for safety evaluation was 289.  Grade 3/4 adverse events (AEs; greater than 5 % incidence) included lymphopenia (16.7 %), hypertension (6.7 %), and leukopenia (6.7 %).  The authors concluded that the combination of ixabepilone and bevacizumab was well-tolerated, with modest activity in 2nd-line or later-line mRCC, but it is not recommended as a therapy without further clinical development; alternative combinations with these agents could be explored in future studies.

Uterine Cancer

Roque and colleagues (2015) described the clinical outcome and tolerability of weekly ixabepilone (16 to 20 mg/m(2) days 1, 8, 15 of a 28-day cycle) ± biweekly bevacizumab (10 mg/kg days 1 and 15) in patients with recurrent/persistent uterine or ovarian/primary peritoneal/fallopian tube cancers. A single-institution retrospective review was performed inclusive of all patients who received greater than or equal to 2 cycles from 01/2010 to 06/2014. Progression-free survival OS were determined using the Kaplan-Meier method. Toxicities were graded according to CTCAEv4.0. Best response was categorized using RECIST or by CA-125 criteria. A total of 60 patients (24 uterine and 36 ovarian cancers) were identified. Patients had received a median of 3.5 (range of 1 to 10) prior lines of chemotherapy. Patients completed a mean of 4.7 ± 2.9 cycles of ixabepilone; 66.7 % (16/24) and 91.7 % (33/36) of patients with uterine and ovarian cancers received concurrent bevacizumab. For uterine cancers, ORR was 41.7 % (12.5 % complete response [CR], 29.2 % PR); median duration of response or stabilization was 7 months (range of 2 to 30). Median PFS and OS were 5.2 and 9.6 months, respectively; PFS and OS were improved in the setting of concurrent bevacizumab (6.5 versus 3.0 months, p = 0.01, HR 0.2, 95 % CI: 0.05 to 0.77; 9.6 versus 4.2 months, p = 0.02, HR 0.58, 95 % CI: 0.04 to 0.74). Similar ORR was observed among ovarian cancers; median PFS/OS were not yet reached. Most toxicities were grade 1/2. The authors concluded that weekly ixabepilone with or without biweekly bevacizumab has promising activity and acceptable toxicity in patients with platinum-/taxane-resistant endometrial and ovarian cancers. They stated that this combination warrants further prospective study in these populations.

In a phase II clinical trial, McCourt and colleagues (2017) determined the ORR and safety profile of ixabepilone in women with recurrent or persistent uterine carcinosarcoma (UCS).  Secondary objectives included PFS and OS.  Exploratory translational objectives included characterization of class III beta tubulin expression and its association with response, PFS, and OS.  Patients had measurable disease; up to 2 prior FDA-approved chemotherapeutic regimens were allowed, but must have included a taxane.  Women received ixabepilone 40 mg/m2 as a 3-hour IV infusion on day 1 of a 21-day cycle.  Treatment was continued until disease progression or unacceptable toxicity occurred.  A total of 42 women were enrolled, with 34 eligible and evaluable.  Median age was 68 years; Eastern Cooperative Oncology Group (ECOG) performance status was 0 in 56 % of women, 38 % had received radiation, and 15 % had received 2 lines of chemotherapy.  Overall ORR was 11.8 % (4/34, 90 % CI: 4.2 to 25.1 %); all were PRs; SD for at least 8 weeks was achieved in 8 patients (23.5 %).  Median PFS and OS were 1.7 months and 7.7 months, respectively, with a median follow-up of 37 months; 6-month PFS was 20.6 %.  Major grade-3 or higher toxicities were neutropenia (47 %), fatigue (15 %), dehydration (15 %), hypertension (15 %), and hyponatremia (15 %); grade-2 peripheral neuropathy was reported in 18 %.  In this small sample size, class III beta tubulin expression in the primary tumor was not associated with the response to ixabepilone, PFS, or OS.  The authors concluded that in this cohort of women, single-agent ixabepilone showed modest but insufficient clinical activity.

McCourt and colleagues (2017) determined the ORR and safety profile of ixabepilone in women with recurrent or persistent uterine carcino-sarcoma (UCS); secondary objectives included PFS and OS.  Exploratory translational objectives included characterization of class III beta tubulin expression and its association with response, PFS, and OS.  Patients had measurable disease; up to 2 prior chemotherapeutic regimens were allowed, but must have included a taxane.  Women received ixabepilone 40 mg/m2 as a 3-hour IV infusion on day 1 of a 21-day cycle.  Treatment was continued until disease progression or unacceptable toxicity occurred.  A total of 42 women were enrolled, with 34 eligible and evaluable.  Median age was 68 years; ECOG performance status was 0 in 56 % of women, 38 % had received radiation, and 15 % had received 2 lines of chemotherapy.  Overall ORR was 11.8 % (4/34, 90 % CI: 4.2 to 25.1 %); all were PRs; SD for at least 8 weeks was achieved in 8 patients (23.5 %).  Median PFS and OS were 1.7 months and 7.7 months, respectively, with a median follow-up of 37 months; 6-month PFS was 20.6 %.  Major grade greater than or equal to 3 toxicities were neutropenia (47 %), fatigue (15 %), dehydration (15 %), hypertension (15 %), and hyponatremia (15 %); grade 2 peripheral neuropathy was reported in 18 %.  In this small sample size, class III beta tubulin expression in the primary tumor was not associated with the response to ixabepilone, PFS, or OS.  The authors concluded that in this cohort of women, single-agent ixabepilone showed modest but insufficient clinical activity.

---

References