A phase II study of a novel oral isotype-selective histone deacetylase (HDAC) inhibitor in patients with relapsed or refractory Hodgkin lymphoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8000-8000 ◽  
Author(s):  
A. Younes ◽  
M. Fanale ◽  
B. Pro ◽  
P. McLaughlin ◽  
S. Neelapu ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Phase Ii ◽  
Single Agent ◽  
Objective Response ◽  
Hdac Inhibitors ◽  
Response Analysis ◽  
Transcriptional Level ◽  
Cell Transplant ◽  
Tumor Reduction ◽  
Refractory Hodgkin Lymphoma

8000 Background: MGCD0103 is a non-hydroxamate, isotype-selective, inhibitor of human HDACs. Abnormal regulation of HDAC activity is associated with malignant disease in humans, and small molecule HDAC inhibitors are a novel drug class with anticancer potential. Their proposed anti-Hodgkin activity is through regulation of aberrant gene expression at the transcriptional level by inhibiting proliferation, inducing apoptosis, and/or initiating differentiation in cancer cells. Methods: A phase II trial of MGCD0103 (110 mg 3x/week in 4- week cycles) is ongoing in patients (pts) with relapsed/refractory Hodgkin Lymphoma (RRHL). The primary endpoint is a composite of objective response and stable disease. Results: As of Dec 15th, 2006, 18 pts out of a planned 12–35 have been enrolled; median age 28 (range: 21–62). All pts were previously treated with autologous and/or allogeneic stem cell transplant. The median number of cycles received to date is 2 (range: 1–4). Seven pts have completed =8 weeks (2 cycles) of therapy and are evaluable for response analysis; 5 of these had tumor reduction ranging between 21% and 70% by CT, which is associated with a significant reduction in FDG-PET activity in 4 pts. Of the 18 pts, 5 have had dose reductions/discontinuations due to: mucositis (n=1); fatigue/nausea/diarrhea (n=1); nausea/vomiting (n=1); fatigue (n=1) and pancreatitis/hypotension (n=1). Significant HDAC inhibition (>20% of total activity), was seen in PBMCs from 7/9 pts with samples. Treatment is ongoing in 14 pts; including those with tumor reduction. Criteria have been met to expand to the second stage of the study (>1 response demonstrated in the first 12 patients). Conclusions: Preliminary results suggest that single-agent MGCD0103 demonstrates significant anti-tumor activity in RRHL and is well tolerated at a Phase II dose of 110mg in this ongoing trial. No significant financial relationships to disclose.

mTOR Inhibition for Relapsed or Refractory Hodgkin Lymphoma: Promising Single Agent Activity with Everolimus (RAD001).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2555-2555 ◽  
Author(s):  
Patrick B. Johnston ◽  
Steven M. Ansell ◽  
Joseph P. Colgan ◽  
Thomas M. Habermann ◽  
David J. Inwards ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Phase Ii ◽  
Response Rate ◽  
Single Agent ◽  
Mtor Inhibitors ◽  
Cell Transplant ◽  
Mtor Inhibition ◽  
Treatment Regimens ◽  
Common Grade ◽  
Grade 3

Abstract Background: mTOR inhibition has produced responses in mantle cell lymphoma as well as other non-Hodgkin lymphomas. This phase II study tested the oral mTOR inhibitor everolimus (RAD001, Novartis Pharmaceuticals) in simultaneous two-stage phase II lymphoma studies, including one arm involving Hodgkin lymphoma. The goals were to learn the toxicity profile and to assess the anti-tumor response. A total of 17 patients with Hodgkin lymphoma were enrolled in the uncommon arm at completion of enrollment. Methods: Patients (pts) received 10 mg PO daily for each 28 day cycle (up to 12, with a possible extension in responders) and restaged after 2, 6, and 12 cycles. The primary endpoint is the confirmed response rate, including CR, CRu or PR. Results: The median age of the 17 pts with Hodgkin lymphoma was 37 yrs (range: 27–68), with a median of 6 (range, 4–14) prior therapies. Fourteen pts (82.4%) had a prior stem cell transplant (SCT). Pts completed a median of 6 (range, 1–13) cycles of therapy. Fifteen of 17 patients were evaluable for response as of this analysis. The overall response rate was 47% (7/15), all partial responses. Ten patients are continuing on study while 6 have gone off due to disease progression and 1 due to other reasons. Common grade 3 adverse events (AEs) include thrombocytopenia (5 pts), anemia (5 pts) and alkaline phosphatase elevation (1 pts). 1 patient was reported to have grade 4 neutropenia. Conclusions: Oral everolimus has promising activity with acceptable toxicity in Hodgkin lymphoma. These results provide the rationale for additional studies with this novel class of agents and to integrate mTOR inhibitors into salvage treatment regimens for Hodgkin lymphoma.

scholarly journals The Oral Mtor Inhibitor Everolimus in Relapsed and Refractory Hodgkin Lymphoma- Compassionate Use in 8 Centers in Brazil

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5107-5107
Author(s):  
Talita Silveira Da Rocha ◽  
Sergio Costa Fortier ◽  
Nelson Siqueira de Castro ◽  
Marcia T Delamain ◽  
José Salvador Oliveira ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Single Agent ◽  
Antineoplastic Agent ◽  
Mammalian Target Of Rapamycin ◽  
Signal Transduction Pathway ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Phosphatidylinositol 3 Kinase ◽  
Compassionate Use ◽  
Refractory Hodgkin Lymphoma

Abstract Purpose- Everolimus is an oral antineoplastic agent that targets the raptor mammalian target of rapamycin (mTORC1). The phosphatidylinositol 3-kinase/mTOR signal transduction pathway has been demonstrated to be activated in tumor samples from patients with Hodgkin Lymphoma (HL). The goal of this study was to evaluate the response, time of response, toxicity and overall survival in patients with refractory disease using everolimus out of clinical trial, in a compassionate use. Patients and Methods- Patients were eligible if they had refractory and active Hodgkin disease. Patients received everolimus 10 mg PO daily. Dose reductions were allowed. Time to response assessement was defined by each center until progression (this was defined by each doctor, some have considered to keep the drug until clinical progression and not radiological progression of the disease). Patients could remain on drug until progression or toxicity. Results- Thirty three patients were enrolled. Median age at the time of everolimus start was 29 years (range, 20-70). Patients had received a median of 5 prior therapies (range, 3-7) , 81% had undergone prior autologous stem cell transplant and 4 patients had undergone alogenic trasnplantation. The ORR was 51% (95% CI: 24-71%) with 14 patients achieving a PR, 3 patient achieving a CR and 10 with stable disease. Thirteen patients used the drug for more than 1 year. Patients received a median of 14 cycles of therapy and 3 remains on therappy at 36 months showing a great tolerability of the drug. The median DR for the responders (CR/PR) was 10 months. The most commons site effects were trombocitopenia and hypercholesterolemia. Three patients had pulmonar toxicity. The adverse events grade III and IV ocurred in 30% of the patients. Conclusions- Everolimus has single-agent activity in relapsed/refractory HL, even in real lyfe and clinical practice and provides proof-of-concept that targeting the mTOR pathway in HL is clinically relevant. Disclosures Off Label Use: everolimus for refractory hodgkin lymphoma.

Resminostat In Relapsed or Refractory Hodgkin Lymphoma: Initial Results of the SAPHIRE Phase II Trial with a Novel Oral Histone Deacetylase (HDAC) Inhibitor.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2811-2811 ◽  
Author(s):  
Jan Walewski ◽  
Ewa Paszkiewicz-Kozik ◽  
Gabriela Borsaru ◽  
Andreea Moicean ◽  
Agnieszka Warszewska ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Phase Ii ◽  
Hdac Inhibitor ◽  
Objective Response ◽  
Clinical Activity ◽  
High Dose ◽  
Open Label ◽  
Hematopoietic Stem ◽  
Pet Ct ◽  
Refractory Hodgkin Lymphoma

Abstract Abstract 2811 Resminostat (4SC-201) is a novel pan-HDAC inhibitor that has shown anti-tumor activity in a broad panel of preclinical models and revealed a very favorable safety and promising efficacy profile in patients with various solid tumor types in an initial Phase I trial. Resminostat is currently under investigation in a number of Phase II clinical trials. The SAPHIRE study evaluates the therapeutic activity of resminostat in relapsed/refractory Hodgkin Lymphoma (HL) patients after high dose chemotherapy and autologous hematopoietic stem cell transplantation. The trial is designed as an open-label, single-arm international trial with a Simon Minimax design. Resminostat is administered orally at a once daily dose of 600 mg in 2-week cycles consisting of 5 consecutive days treatment followed by a 9 day treatment free period. Dose delay and reduction is allowed for management of adverse events. Patients undergo assessment of disease status by computed tomography in combination with positron emission tomography (PET/CT), as recommended by the International Working Group (IWG) criteria for the evaluation of HL. PET/CT scans are conducted after cycle 3 and cycle 6 and thereafter every 4th cycle during an optional follow-up treatment period in which patients may remain on treatment until disease progression or occurrence of intolerance to protocol therapy. The primary endpoint of the study is the estimation of overall objective response rate (OOR), secondary endpoints include time to response (TTR), duration of response (DOR), safety and tolerability and the study of drug regulated biomarkers in this patient cohort. As of July 2010, 19 patients with advanced HL have been enrolled in the 1st Simon stage of the study. Treatment was well tolerated with common related grade 2 –3 AEs being anemia and thrombocytopenia that were well manageable by dose modification or symptomatic treatment. Analysis of PET/CT data through an independent central assessment committee confirmed the achievement of the clinical activity requirements for the advancement of the trial into the 2nd Simon recruitment phase. Updated clinical data of this ongoing study on the efficacy and safety of the HDAC inhibitor resminostat in relapsed/refractory HL patients will be presented at the meeting. Disclosures: Walewski: 4SC AG: Consultancy. Warszewska:4SC AG: Consultancy. Strobel:4SC AG: Consultancy. Biggi:4SC AG: Consultancy. Hauns:4SC AG: Employment. Mais:4SC AG: Employment. Henning: 4SC AG: Employment. Hentsch:4SC AG: Employment.

SGN-30 (Anti-CD30 mAb) Has a Single-Agent Response Rate of 21% in Patients with Refractory or Recurrent Systemic Anaplastic Large Cell Lymphoma (ALCL).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2718-2718 ◽  
Author(s):  
Andres Forero-Torres ◽  
STeven H. Bernstein ◽  
Ajay Gopal ◽  
Francine Foss ◽  
John P. Leonard ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Performance Status ◽  
Single Agent ◽  
Objective Response ◽  
Cell Transplant ◽  
Cutaneous Lesions ◽  
Ecog Performance Status ◽  
Good Tolerability ◽  
Poor Prognostic Factor

Abstract SGN-30 is a monoclonal antibody directed against the CD30 antigen expressed on some hematologic malignancies. Based on encouraging phase I data, a multicenter phase II study was conducted treating patients with refractory or recurrent CD30-positive ALCL with an ECOG performance status of ≤ 2. Thirty-nine patients (24M, 15F) with ALCL were enrolled, with a median age of 57 (range 23–82) and a median of 3 prior therapies (range 2–5). Nine patients had previously received a stem cell transplant. Eighty-five percent of tumors were negative for ALK, a poor prognostic factor. SGN-30 was administred at 6 mg/kg/wk (90 minute infusion, premedications were not required) for 6 consecutive weeks. After 24 patients were enrolled, the dose was escalated to 12 mg/kg/wk in subsequent patients. (Patients with stable disease or objective response were eligible to receive additional cycles of SGN-30. Five patients received ≥ 2 cycles of SGN-30.) Response assessments, as determined by CT scans, were performed 2 weeks after the last infusion. Best response is shown below: CR PR SD PD Pending Eval ORR *Both CRs have ongoing durations of >365 days; both patients received additional cycles of SGN-30. **PRs had durations of 27, 53, 139 and 167 days; two additional patients have ongoing durations of 86+ and 25+ days. ***Three SDs have ongoing durations of 96+, 365+, and 365+ days. Two additional patients had SD for 71 and 174 days. 2* 6** 5*** 24 2 21% Three drug-related toxicities ≥ Grade 3 were reported (each was considered possibly related to SGN-30): 1) lymphopenia, 2) catheter related infection and 3) urticaria. No other significant hematologic or biochemical toxicities have been observed. There was one definitely related serious adverse event (Grade 2) in a patient who experienced a transient exacerbation of his cutaneous lesions after 2 doses of SGN-30 but achieved a partial response after continuing on study. This phase II study represents one of the largest prospectively designed trials in relapsed/refractory ALCL and demonstrates good tolerability and clinically meaningful antitumor activity of SGN-30, especially in ALK negative patients who have a particularly poor prognosis.

Brentuximab Vedotin Plus Bendamustine for Pediatric Patients with Relapsed/Refractory Hodgkin Lymphoma: A Multi-Institution Retrospective Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-35
Author(s):  
Christopher J. Forlenza ◽  
Nitya Gulati ◽  
Audrey Mauguen ◽  
Michael J. Absalon ◽  
Sharon M. Castellino ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Salvage Therapy ◽  
Pediatric Patients ◽  
Single Agent ◽  
Objective Response ◽  
Brentuximab Vedotin ◽  
High Dose ◽  
Cell Transplant ◽  
First Line ◽  
Grade 3

Background: Pediatric patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL) are often curable through a combination of salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT). Complete response (CR) to salvage treatment prior to HSCT is associated with superior outcomes, therefore optimal salvage treatments need to be identified. Brentuximab vedotin (BV), an antibody-drug conjugate combining an anti-CD30 murine/human chimeric monoclonal antibody covalently linked by an enzyme cleavable peptide to monomethyl auristatin E, and bendamustine, a fusion hybrid molecule containing the purine analogue fludarabine and the alkylating nitrogen mustard, are novel agents that have demonstrated potency as single-agent therapies for patients with R/R HL. Recently, the combination of BV and bendamustine proved to be highly active in adults with R/R HL. However, safety and efficacy data for pediatric patients are lacking. Patients and Methods: We performed a multi-institution retrospective review of pediatric patients with R/R HL <21 years of age treated with BV/bendamustine. Patients received BV (1.8mg/kg) on Day 1 with bendamustine (90mg/m2) on Days 1 and 2 of 3-week cycles. Response was assessed utilizing Lugano criteria. Twenty-nine patients with a median age of 16 years (range 10 to 20 years) were identified across 3 institutions. Ten patients were classified as having refractory disease and 19 with relapsed disease, with 14/19 patients having relapsed less than a year from the completion of initial therapy. Twenty-one patients received BV/bendamustine as first line salvage therapy. Eight patients (28%) previously received radiation therapy (RT), 4 patients (14%) received prior BV and 4 patients (14%) had ASCT as part of prior therapy. Results: Patients received a median of 3 cycles of BV/bendamustine (range 2-7). Overall, 18 (62%) patients achieved a CR (95%CI: 42 to 79%). An objective response (OR) was observed in 23 patients (ORR 79%) (95%CI: 60 to 92%). Notably, response rates were comparable among patients with relapsed (CR/ORR: 63/79%) or refractory (CR/ORR: 60/80%) disease. Among responders, 15 (65%) achieved best response within 2 cycles. CR and OR rates in patients receiving BV/bendamustine as first-line salvage therapy versus second-line salvage or greater was 67/81% and 50/75%, respectively. The most common grade 3 or 4 toxicities were hematologic (neutropenia (n=13), anemia (n=4), thrombocytopenia (n=4)). Three patients experienced grade 3 infusion reactions. Two patients proceeded with BV/bendamustine following desensitization protocols and 1 patient continued therapy with single-agent bendamustine. Sixteen patients received a consolidative transplant following BV/bendamustine (13 autologous, 3 allogeneic), 5 patients received consolidative RT, and 10 patients received post-transplant consolidation with BV. For the entire cohort, the 3-year post-BV/bendamustine event-free and overall survival was 65% (95%CI: 46 to 85%) and 89% (95%CI: 74 to 100), respectively. Conclusions: Combination therapy with BV/bendamustine for pediatric patients with R/R HL compares favorably with currently accepted salvage regimens in terms of response and tolerability. These results support evaluation of this regimen in a multi-center prospective clinical trial. Disclosures Absalon: Jazz Pharmaceuticals: Research Funding. Shukla:Syndax Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees.

How I treat relapsed and refractory Hodgkin lymphoma

Blood ◽  
2011 ◽  
Vol 117 (16) ◽  
pp. 4208-4217 ◽  
Author(s):  
John Kuruvilla ◽  
Armand Keating ◽  
Michael Crump
Keyword(s):  
Hodgkin Lymphoma ◽  
Single Agent ◽  
Allogeneic Transplantation ◽  
Autologous Stem Cell Transplant ◽  
Salvage Chemotherapy ◽  
Cell Transplant ◽  
Primary Therapy ◽  
Refractory Disease ◽  
Refractory Hodgkin Lymphoma

AbstractRelapsed or refractory Hodgkin lymphoma is a challenging problem for clinicians who treat hematologic malignancies. The standard management of these patients should include the use of salvage chemotherapy followed by autologous stem cell transplant (ASCT) in patients who are chemotherapy sensitive. Open issues in this area include the role of functional imaging, the specific chemotherapy regimen to be used before ASCT, and the role of consolidative radiotherapy. Some patients will not be eligible for ASCT, and alternative approaches with conventional chemotherapy alone or with salvage radiotherapy should be considered. Prognostic factors for relapsed/refractory disease have been identified but generally are not used as a part of risk-adapted therapy. Allogeneic transplantation may offer the potential of a graft-versus-lymphoma effect, but this therapy has significant toxicity and results in few long-term disease-free survivors; hence, it should only be offered in the context of disease-specific clinical trials. An expanding list of novel drugs has exhibited promising single-agent activity. Patients have effective options beyond primary therapy, and continued progress through controlled trials remains a tangible goal in the treatment of relapsed and refractory disease.

scholarly journals DDRE-06. CELLULAR STRESS RESPONSE IN DIPG THERAPY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii62-ii62
Author(s):  
Sreepradha Sridharan ◽  
Arif Harmanci ◽  
Robert Siddaway ◽  
Tara Dobson ◽  
Jyothishmathi Swaminathan ◽  
...  
Keyword(s):  
Stress Response ◽  
Single Cell ◽  
Synthetic Lethality ◽  
Clonal Evolution ◽  
Single Agent ◽  
Objective Response ◽  
Hdac Inhibitors ◽  
Pediatric Brain Tumor ◽  
Dominant Negative ◽  
Cellular Stress Response

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable pediatric brain tumor of the pons and brainstem. Therefore, there is a desperate need for new therapeutics. Genomic profiling of tumors identified a highly prevalent dominant negative somatic mutation at lysine (K)-27 in histone genes HIST1H3B and H3F3A. Clonal evolution modeling suggests these mutations are truncal, and studies have demonstrated their contribution to tumorigenesis. ONC201, a first-in-class DRD2 antagonist and ClpP agonist is an anticancer drug developed by Oncoceutics, which targets the unfolded protein response (UPR) and integrated stress response (ISR) signaling and is actively being investigated in patients with recurrent H3 K27M-mutant gliomas. In adults with recurrent glioma, single agent studies showed benign-safety, no dose-limiting toxicities and a durable objective response when administered orally. In addition, intra-tumoral drug levels exceeded therapeutic thresholds, and induced tumor cell apoptosis. Based on this and response seen in a pediatric patient with DIPG for whom compassionate use of ONC201 was approved, a multi-arm, non-randomized multi-institutional Phase I clinical trial (NCT03416530) is actively accruing patients. However, the strength of UPR and ISR in DIPGs and their effect on DIPG response to ONC201 is not known. Our group employed bulk/single cell transcriptomic and single cell proteomic approaches to demonstrate substantial heterogeneity in UPR and ISR signaling in human DIPG samples. Consistent with this, DIPG cell lines exhibited considerable variability in sensitivity to ONC201. Single cell profiling identified tumor sub-populations with significant proliferative capacity even after ONC201 exposure. Incomplete response promotes recurrence. To target these cells, we performed a synthetic lethality screen with a library of 360 FDA-approved CNS penetrant compounds, which identified HDAC inhibitors and DNA damage-inducing chemotherapy as having synergy with ONC201. Thus, we suggest that tumor heterogeneity impacts sensitivity to ONC201 and that this can be reduced by combination treatments.

scholarly journals Phase II study of selumetinib, an orally active inhibitor of MEK1 and MEK2 kinases, in KRASG12R-mutant pancreatic ductal adenocarcinoma

2021 ◽  
Author(s):  
Cara Kenney ◽  
Tricia Kunst ◽  
Santhana Webb ◽  
Devisser Christina ◽  
Christy Arrowood ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Phase Ii ◽  
Pancreas Cancer ◽  
Phase Ii Study ◽  
Mapk Pathway ◽  
Single Agent ◽  
Objective Response ◽  
Ductal Adenocarcinoma ◽  
Active Inhibitor ◽  
Orally Active

SummaryBackground Preclinical evidence has suggested that a subset of pancreatic cancers with the G12R mutational isoform of the KRAS oncogene is more sensitive to MAPK pathway blockade than pancreatic tumors with other KRAS isoforms. We conducted a biomarker-driven trial of selumetinib (KOSELUGO™; ARRY-142886), an orally active, allosteric mitogen-activated protein kinase 1 and 2 (MEK1/2) inhibitor, in pancreas cancer patients with somatic KRASG12R mutations. Methods In this two-stage, phase II study (NCT03040986) patients with advanced pancreas cancer harboring somatic KRASG12R variants who had received at least one standard-of-care systemic therapy regimen received 75 mg selumetinib orally twice a day until disease progression or unacceptable toxicity occurred. The primary outcome of the study was best objective response (BOR). Results From August 2017 to February 2018 a total of 8 patients with confirmed somatic KRASG12R mutations and a median age of 61.5 years were treated with selumetinib. Seven out of eight (87.5%) had received two or more lines of prior systemic chemotherapy. After a median follow-up period of 8.5 months (range 2 to 20), three patients had stable disease for more than 6 months while receiving selumetinib. No patients achieved an objective partial response. Median progression-free survival (PFS) was 3.0 months (95% CI, 0.8–8.2) and median overall survival (OS) 9 months (95% CI, 2.5–20.9). Conclusion This study in heavily pre-treated pancreatic adenocarcinoma patients suggests alternative strategies beyond single agent MEK inhibition are required for this unique, molecular subset of pancreatic cancer patients. The trial was registered on February 2nd, 2017 under identifier NCT03040986 with ClinicalTrials.gov.

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