A phase I study of panobinostat in pediatric patients with refractory solid tumors, including CNS tumors

Wood, Paul; Strong, Robyn; McArthur, Grant A.; Michael, Michael; Algar, Elizabeth; Muscat, Andrea; Rigby, Lin; Ferguson, Melissa J; Ashley, David M.

doi:10.1007/s00280-018-3634-4

Cited by 28 publications

(21 citation statements)

References 27 publications

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“…Other standard of care drugs were not eligible (e.g., topotecan and doxorubicin) as the EC50s were too high to be achieved in vivo. Six drugs of the HDAC inhibitor group were active against HPG-RBG1 ( Figure 5), but only panobinostat was selected for further synergistic evaluations as it has already been tested as part of combination treatments in preclinical models of pediatric tumors and published pharmacokinetic data supports that the EC50 (67.2 nM) would be clinically attainable [17][18][19][20].…”

Section: In Vitro and In Vivo Pharmacological Sensitivitymentioning

confidence: 99%

Clinical, Genomic, and Pharmacological Study of MYCN-Amplified RB1 Wild-Type Metastatic Retinoblastoma

Zugbi

Ganiewich

Bhattacharyya

et al. 2020

Cancers

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An uncommon subgroup of unilateral retinoblastomas with highly aggressive histological features, lacking aberrations in RB1 gene with high-level amplification of MYCN (MCYNamplRB1+/+) has only been described as intra-ocular cases treated with initial enucleation. Here, we present a comprehensive clinical, genomic, and pharmacological analysis of two cases of MCYNamplRB1+/+ with orbital and cervical lymph node involvement, but no central nervous system spread, rapidly progressing to fatal disease due to chemoresistance. Both patients showed in common MYCN high amplification and chromosome 16q and 17p loss. A somatic mutation in TP53, in homozygosis by LOH, and high chromosomal instability leading to aneuploidy was identified in the primary ocular tumor and sites of dissemination of one patient. High-throughput pharmacological screening was performed in a primary cell line derived from the lymph node dissemination of one case. This cell line showed resistance to broad spectrum chemotherapy consistent with the patient’s poor response but sensitivity to the synergistic effects of panobinostat–bortezomib and carboplatin–panobinostat associations. From these cells we established a cell line derived xenograft model that closely recapitulated the tumor dissemination pattern of the patient and served to evaluate whether triple chemotherapy significantly prolonged survival of the animals. We report novel genomic alterations in two cases of metastatic MCYNamplRB1+/+ that may be associated with chemotherapy resistance and in vitro/in vivo models that serve as basis for tailoring therapy in these cases.

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Section: In Vitro and In Vivo Pharmacological Sensitivitymentioning

confidence: 99%

Clinical, Genomic, and Pharmacological Study of MYCN-Amplified RB1 Wild-Type Metastatic Retinoblastoma

Zugbi

Ganiewich

Bhattacharyya

et al. 2020

Cancers

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“…HDAC inhibitors have been evaluated in clinical trials for adults with sarcomas and have demonstrated limited success as monotherapy [82]. In pediatrics, HDAC inhibitors have been evaluated as single agents in phase 1 clinical trials which included patients with RMS and while these agents were well tolerated, there were no objective responses reported [84][85][86][87][88]. These agents may be more effective in combination with chemotherapy or other targeted agents, and there is an ongoing clinical trial for individuals with RMS aged 16 years and older studying the HDAC inhibitor mocetinostat in combination with vinorelbine (NCT04299113).…”

Section: Histone Deacetylase Inhibitorsmentioning

confidence: 99%

Prioritization of Novel Agents for Patients with Rhabdomyosarcoma: A Report from the Children’s Oncology Group (COG) New Agents for Rhabdomyosarcoma Task Force

Pacenta

Allen‐Rhoades

Langenau

et al. 2021

JCM

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Rhabdomyosarcoma is the most common soft tissue sarcoma diagnosed in children and adolescents. Patients that are diagnosed with advanced or relapsed disease have exceptionally poor outcomes. The Children’s Oncology Group (COG) convened a rhabdomyosarcoma new agent task force in 2020 to systematically evaluate novel agents for inclusion in phase 2 or phase 3 clinical trials for patients diagnosed with rhabdomyosarcoma, following a similar effort for Ewing sarcoma. The task force was comprised of clinicians and basic scientists who collectively identified new agents for evaluation and prioritization in clinical trial testing. Here, we report the work of the task force including the framework upon which the decisions were rendered and review the top classes of agents that were discussed. Representative agents include poly-ADP-ribose polymerase (PARP) inhibitors in combination with cytotoxic agents, mitogen-activated protein kinase (MEK) inhibitors in combination with type 1 insulin-like growth factor receptor (IGFR1) inhibitors, histone deacetylase (HDAC) inhibitors, and novel cytotoxic agents.

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“…Wood et al that was performed in pediatric patients with solid tumor, panobinostat was used as 10 mg dose which was well tolerated by pediatric patients. 17 We used etoposide and doxorubicin as the concomitant chemotherapy regimen in order to prevent multidrug resistance. Additionally, the study of Guan Wang et al on neuroblastoma cells revealed that panobinostat increases the cytotoxic effects of doxorubicin or etoposide on high-risk neuroblastoma cells.…”

Section: Case Presentationmentioning

confidence: 99%

Successful treatment of refractory metastatic neuroblastoma with panobinostat in combination with chemotherapy agents and iodine-131-meta-iodobenzylguanidine therapy

Zareifar

Shakibazad

Zekavat

et al. 2019

J Oncol Pharm Pract

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Introduction Neuroblastoma commonly required multimodal therapy containing surgery, chemotherapy, radiotherapy, and immunotherapy. Case report In our case, who had refractory metastatic neuroblastoma, we use histone deacetylase inhibitor (panobinostat) in combination with chemotherapy agents and iodine-131-meta-iodobenzylguanidine (MIBG) therapy. Management and outcome This approach leads to successfully treat the patient. MIBG scan and bone marrow examination after therapy revealed no evidence of tumor. Now, she underwent autologous transplantation six months ago and free of tumor. Conclusion Panobinostat can cause apoptosis induction in refractory metastatic neuroblastoma in combination with MIBG therapy and chemotherapy.

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A phase I study of panobinostat in pediatric patients with refractory solid tumors, including CNS tumors

Abstract: A significant biological effect of panobinostat, measured by acetylation status of histone H3 and H4, was achieved at a dose of 15 mg/m. PK data and drug tolerability at 15 mg/m was similar to that previously published.

Cited by 28 publications

References 27 publications

Clinical, Genomic, and Pharmacological Study of MYCN-Amplified RB1 Wild-Type Metastatic Retinoblastoma

Clinical, Genomic, and Pharmacological Study of MYCN-Amplified RB1 Wild-Type Metastatic Retinoblastoma

Prioritization of Novel Agents for Patients with Rhabdomyosarcoma: A Report from the Children’s Oncology Group (COG) New Agents for Rhabdomyosarcoma Task Force

Successful treatment of refractory metastatic neuroblastoma with panobinostat in combination with chemotherapy agents and iodine-131-meta-iodobenzylguanidine therapy

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