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ABI-009

From EverybodyWiki Bios & Wiki






We have updated our draft per recommendations and re-submitted.

( 5/28/2018).

ABI-009 (nab-rapamycin, albumin-bound rapamycin nanoparticles) is a human albumin-bound rapamycin, also known as nab-rapamycin. ABI-009 is comprised of albumin-bound rapamycin nanoparticles with a mean particle size of approximately 88 nanometers.

ABI-009 is an investigational therapeutic agent, currently in phase 1 and 2 clinical trials for the therapy of malignant perivascular epithelioid cell carcinoma (PEComa), soft-tissue sarcomas, colorectal cancer, nonmuscle-invasive bladder cancer (NMIBC), glioma/glioblastoma, various childhood cancers, and pulmonary arterial hypertension (PAH).

Mechanism of action; the mTOR pathway[edit]

Sirolimus (rapamycin), the active pharmaceutical ingredient in ABI-009, is a potent inhibitor of the mTOR (mammalian target of rapamycin) pathway. The mTOR pathway is a central regulator of cell metabolism and physiology, and senses cellular nutrient, oxygen, and energy levels.1 mTOR also plays essential roles in the proliferation of lymphocytes, vascular smooth muscle cells, endothelial cells, and neuronal development.2,3 Mutations, and thus abnormal activation of the mTOR pathway, underlie a number of diseases with chronic inflammatory features. Therefore, inhibition of this pathway has been an important

Clinical trials with ABI-009[edit]

Perivascular epithelioid cell tumors (PEComa)[edit]

A multi-center phase 2 registrational clinical trial is investigating the efficacy and safety of ABI-009 in patients with advanced malignant PEComa, for which surgery is not an option (NCT02494570). This study is in part funded through a grant from the Food and Drug Administration (FDA) Office of Orphan Products Development (OOPD).

PEComas are ultra-rare mesenchymal tumors that can occur in any parts of the body, with most commonly in the abdominal cavity, pelvic region (uterus in women), and the gastrointestinal tract. The most common types of PEComas are angiomyolipoma (AML), Lymphangioleiomyomatosis (LAM), and clear cell sugar tumor (CCST). Less well-characterized PEComas of a variety of anatomic origins are called PEComa- not otherwise specified (PEComa-NOS).

Soft-tissue sarcomas (STS)[edit]

A phase 1b study sponsored by the Sarcoma Oncology Center is currently evaluating safety and potential anti-tumor activity of ABI-009 in combination with nivolumab in patients with advanced pleomorphic sarcoma, liposarcoma, chondrosarcoma, osteosarcoma, and Ewing sarcoma (NCT03190174). Soft tissue sarcoma is a relatively rare neoplasm, which includes a diversity of histological subtypes and occurs with an incidence of about 1% of all adult cancers. Surgical resection is the standard for localized disease, along with radiation therapy for unresectable sarcomas. However, recurrence rate is high (~50%) and treatment options for metastatic/relapsed STS are limited.4

Colorectal cancer[edit]

A multi-center phase 1/2 clinical study is investigating the efficacy and safety of ABI-009 in combination with mFOLFOX6 and bevacizumab as first-line therapy in patients with advanced or metastatic colorectal cancer (NCT03439462)

Colorectal cancer is the 3rd most common cancer and one of the leading causes of death among cancer types.5 In the early stage, colorectal cancer often does not present symptoms and usually becomes symptomatic when it progresses to more advanced stages. Surgery is the most common treatment for cancers that have not spread, and chemotherapy and/or targeted therapy is given for patients whose cancer metastasized. However, the 5-year survival rate is still a dismal 14% for patients with metastatic colorectal cancer (mCRC).5

Nonmuscle-invasive bladder cancer (NMIBC)[edit]

The efficacy and safety ABI-009 is being evaluated in a phase 1/2 study funded in part by the National Institute of Health (NIH, R42CA171552) in patients with BCG refractory or recurrent NMIBC. In the phase 2 portion of the study, ABI-009 is combined with gemcitabine NCT02009332). The standard first-line treatment for NMIBC (Tis, carcinoma in situ [CIS], Ta or T1) is intravesical BCG, which elicits a nonspecific local immune response. Up to 50% of patients treated with intravesical therapy for high-risk NMIBC or CIS will recur.6 There is no accepted and/or efficacious standard second-line regimen available currently. Because of the lack of targeted therapeutic options, patients who fail to respond to standard intravesical therapies are usually left with radical cystectomy.

Pediatric solid tumors[edit]

A Children's Oncology Group (COG) / National Cancer Institute (NCI) sponsored phase 1 trial is currently evaluating the safety and efficacy of ABI-009 in combination with irinotecan and temozolomide in children with recurrent or refractory solid tumors, including CNS tumors NCT02975882). Relapsed/refractory pediatric solid tumors are a major cause of morbidity and mortality in pediatric oncology with few effective treatment options.

Glioma and glioblastoma[edit]

A phase 2 clinical study investigating ABI-009 combination regimens or as single agent in patients with recurrent high-grade glioma or newly diagnosed glioblastoma (NCT03463265). Gliomas comprise about 30% of all brain and central nervous system tumors, and 80% of all malignant brain tumors. Tumors.7 High-grade gliomas tend to grow rapidly and spread faster than tumors of a lower grade. The most common grade 3 tumor is anaplastic astrocytoma and the most common grade 4 tumor is glioblastoma. Glioblastoma remains a deadly disease with currently limited treatment options. The median survival is only 15 months from initial diagnosis for patients with newly diagnosed GBM, with a 2-year survival rate of 27% and 5-year survival rate less than 5%. 8,9

Pulmonary arterial hypertension (PAH)[edit]

A phase 1 study is currently investigating the safety and potential efficacy of ABI-009 in patients with severe pulmonary hypertension PAH (NCT02587325). PAH is a rare, debilitating, and fatal disease for which there is currently no cure. The number of patients living with the disease in the US is estimated to be between 10,000 and 20,000; however, PAH is likely under diagnosed.10

References[edit]

  1. Corradetti MN, Guan KL. Upstream of the mammalian target of rapamycin: do all roads pass through mTOR? Oncogene 2006;25:6347-60.
  2. Zohlnhofer D, Nuhrenberg TG, Neumann FJ, et al. Rapamycin effects transcriptional programs in smooth muscle cells controlling proliferative and inflammatory properties. Mol Pharmacol 2004;65:880-9.
  3. Garza-Lombo C, Gonsebatt ME. Mammalian Target of Rapamycin: Its Role in Early Neural Development and in Adult and Aged Brain Function. Front Cell Neurosci 2016;10:157.
  4. Wagner MJ, Amodu LI, Duh MS, et al. A retrospective chart review of drug treatment patterns and clinical outcomes among patients with metastatic or recurrent soft tissue sarcoma refractory to one or more prior chemotherapy treatments. BMC Cancer 2015;15:175.
  5. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin 2017;67:7-30.
  6. Kim JC, Steinberg GD. The limits of bacillus Calmette-Guerin for carcinoma in situ of the bladder. J Urol 2001;165:745-56.
  7. Goodenberger ML, Jenkins RB. Genetics of adult glioma. Cancer Genet 2012;205:613-21.
  8. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-96.
  9. Khosla D. Concurrent therapy to enhance radiotherapeutic outcomes in glioblastoma. Annals of translational medicine 2016;4:54.
  10. Peacock AJ, Murphy NF, McMurray JJ, Caballero L, Stewart S. An epidemiological study of pulmonary arterial hypertension. Eur Respir J 2007;30:104-9.


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