A phase II study of single agent mocetinostat, an oral isotype-selective histone deacetylase (HDAC) inhibitor, in patients with diffuse large cell B-cell (DLBCL) and follicular (FL) lymphomas.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8535-8535 ◽  
Author(s):  
Michael Crump ◽  
Charalambos Andreadis ◽  
Sarit E. Assouline ◽  
David Rizzieri ◽  
Amanda Copeland ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Hdac Inhibitor ◽  
Single Agent ◽  
Objective Response ◽  
Study Drug ◽  
Clinical Activity ◽  
Duration Of Treatment ◽  
Open Label ◽  
Cardiac Symptoms

8535 Background: Mocetinostat (MGCD0103) is an orally available, isotype-selective, non-hydroxamate HDAC inhibitor targeting HDACs 1,2, 3 and 11 with single-agent activity in Hodgkin’s lymphoma and in AML and MDS (in combination with 5-azacitidine). More than 430 patients have been treated to date. Methods: This open-label, phase II trial enrolled patients with DLBCL and FL. Patients received mocetinostat at doses ranging from 70-110 mg 3x/wk every 28 days. Anticancer activity, safety, pharmacokinetics and pharmacodynamics were evaluated. Results: Sixty-nine patients with DLBCL (n=41) and FL (n=28) were enrolled for treatment at starting doses of 85-110 mg. Median age was 62 years (range: 32 to 81). Median duration of treatment was ~3 months (range: <1 to 24). Objective response rate in DLBCL and FL, respectively, was 7/41 (17%; including 2 unconfirmed PRs) and 3/28 (11%; including 1 CR). Median time to response was 2.0 mos (range 1.7-21.0) and 5.3 mos (range 4.3-6.0) respectively. Stable disease was achieved by 13/41 (32%) and 14/28 (50%), respectively, for a disease control rate of 49% and 61%, respectively. Mean duration of SD in patients with DBLCL was ~4.5 mos (range 2-12 mos), with 10 patients remaining stable for ≥3 mos. Among FL patients, mean duration of SD was approximately 4.1 mos (range 1.7-13 mos), with 9 patients remaining stable for ≥3 mos. The FL CR occurred in a 62-year-old female with paratracheal, subcarinal and portal target lesions who achieved a PR after 4 cycles and CR after 12 cycles that persisted through the remaining 4 mos on study. Study drug was discontinued for adverse events in 19/69 (28%). Fatigue, weight loss or anorexia were most common (n=4 each). A total of 26 drug-related SAEs were reported among 12 patients (17%; 1-6 events per pt). There were no drug related deaths. Enrollment is complete and final data will be presented. Conclusions: Single-agent mocetinostat has activity in DLBCL and FL. Fatigue, gastrointestinal, and cardiac symptoms are the most common adverse events resulting in discontinuation of dosing. Based on the acceptable tolerability and clinical activity further development is warranted. Clinical trial information: NCT00359086.

A phase II trial of the CDK4/6 inhibitor palbociclib (P) as single agent or in combination with the same endocrine therapy (ET) received prior to disease progression, in patients (pts) with hormone receptor positive (HR+) HER2 negative (HER2−) metastatic breast cancer (mBC) (TREnd trial).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1002-1002 ◽  
Author(s):  
Luca Malorni ◽  
Giuseppe Curigliano ◽  
Alessandro Marco Minisini ◽  
Saverio Cinieri ◽  
Carlo Tondini ◽  
...  
Keyword(s):  
Phase Ii ◽  
Clinical Data ◽  
Single Agent ◽  
Objective Response ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Complete Response ◽  
Clinical Activity ◽  
P Value ◽  
Open Label

1002 Background: P is approved for treatment of HR+/HER2− mBC combined with ET. There is paucity of clinical data of single-agent P in ET resistant pts. Pre-clinical data suggest P may partially reverse endocrine resistance, though this is yet to be tested in pts. Methods: This Phase II, open-label, multicenter study enrolled post-menopausal pts with HR+ HER2− mBC who progressed on 1 or 2 prior ETs. Pts were randomized to P (125 mg/d 3 w on/1 w off) alone or to continue their current ET (aromatase inhibitor or fulvestrant) in combination with P (same schedule as P arm). The primary endpoint was clinical benefit rate (CBR) [complete response (CR), partial response (PR) and stable disease (SD) for > 6 months (mo)]. Secondary endpoints were adverse events (AE) and additional measures of efficacy. A two-stage optimal design assessed treatment activity in each arm assuming activity as CB≥40% (α and β = 10%). Exploratory comparisons were planned for safety and efficacy endpoints. Results: 115 pts were enrolled (ITT population) 58 in the P arm and 57 in the P+ET arm. In both arms, 67% of pts had the study treatment as second line ET, 33% as third line, and about 1/3 of pts also received 1 prior chemotherapy for mBC. CBR was similar in both arms: 54% (95% CI 42 - 67%) with P+ET, and 60% (95% CI 48 -73%) with P alone. Median duration of CB was longer with P+ET (11.5 mo; 95% CI 8.6 – 17.8) than with P (6 mo; 95% CI 3.9 - 9.9) (HR 0.31, 95% CI 0.1 - 0.7, p-value 0.001, exploratory). Objective response rate (ORR; CR, PR) was 11% (95% CI 3 - 19%) and 7% (95% CI 0.4 -13%) with P+ET and P, respectively. PFS was 10.8 mo (95% CI 5.6 - 12.7) with P+ET and 6.5 mo (95% CI 5.4 - 8.5) with P alone (HR 0.69, 95% CI 0.4 - 1.1, p-value 0.13, exploratory). AEs were in line with previous data. Conclusions: Single agent P has clinical activity in ET pre-treated HR+/HER2– mBC pts. The observed increase in PFS and duration of CB with P+ET may suggest that P could reverse resistance to the prior line of ET. Translational studies are ongoing to explore potential biomarkers in this setting. Clinical trial information: NCT02549430.

Targeting HER2 (ERBB2) mutation-positive advanced biliary tract cancers with neratinib: Results from the phase II SUMMIT ‘basket’ trial.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 320-320
Author(s):  
James J. Harding ◽  
James M. Cleary ◽  
David I. Quinn ◽  
Irene Braña ◽  
Victor Moreno ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Study Drug ◽  
Standards Of Care ◽  
Clinical Activity ◽  
Genomic Profiling ◽  
Open Label ◽  
Biliary Tract Cancers

320 Background: Genomic profiling studies have reported somatic HER2 mutations in ~2–5% of biliary tract cancers (BTC). Clinical data from the SUMMIT study demonstrate that neratinib, a pan-HER irreversible tyrosine kinase inhibitor, has encouraging clinical activity in multiple types of HER2-mutant solid tumor malignancies. Methods: SUMMIT is a multi-histology, open-label, phase II ‘basket’ study of neratinib in patients with somatic HER2 mutations (ClinicalTrials.gov NCT01953926). Patients with activating somatic HER2 mutations with different histologies, including BTC, received neratinib monotherapy (240 mg oral daily). Loperamide prophylaxis was mandatory during cycle 1. Efficacy endpoints: objective response rate (ORR, RECIST v1.1); clinical benefit rate (CBR); duration of response; progression-free survival (PFS). Adverse events (AEs) were assessed by CTCAE v4.0. Genomic profiling from fresh/archival tumor tissues and/or plasma cfDNA was performed retrospectively by next-generation sequencing (MSK-IMPACT). Results: As of 3-Sep-2020, 25 patients with HER2-mutant BTC were enrolled: gallbladder (40%); intrahepatic (24%); extrahepatic (20%); ampulla of Vater (16%). 68% of patients received ≥2 systemic regimens (96% received prior gemcitabine-based regimens). The S310F/Y variant accounted for nearly half of HER2 mutations (n=11). Other HER2 mutations: V777L (n=5); L755S (n=2); V842I (n=2); R678Q (n=2). Confirmed ORR in 25 evaluable patients was 12% (95% CI 3–31%) and CBR was 20% (95% CI 7–41%), including 3 confirmed PRs and 2 patients with SD for ≥16 weeks. Tumor shrinkage was observed in multiple HER2-activating mutations and enriched in gallbladder and extrahepatic subtypes of BTC. Median PFS was 2.8 (95% CI 1.1–3.7) months; median overall survival (OS) was 5.4 (95% CI 3.7–11.7) months. Nine (36%) patients (3 of whom with ECOG PS 2) came off study within 28 (range 6–47) days of treatment due to clinical deterioration (unrelated to study drug) followed by death. The most common treatment-related AEs (any grade) were diarrhea (56%) and vomiting (48%). Diarrhea was the most common Grade 3 event (24%); 4 patients (16%) required a neratinib dose reduction; no patients discontinued treatment due to diarrhea. Conclusions: Neratinib is safe and tolerable in patients with advanced BTC patients and somatic HER2 mutations. The antitumor activity of neratinib appears comparable to current standards of care, with similar PFS and OS in heavily pretreated patients. Analysis of co-occurring oncogenic mutations and response is ongoing, and consideration is being given to neratinib-based combination regimens to further improve outcomes in this setting. Clinical trial information: NCT01953926.

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.

Imexon (AOP 99.0001) for Treatment of Relapsed or Refractory Multiple Myeloma: A Phase I/II Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5195-5195
Author(s):  
Thomas M. Moehler ◽  
Anatoli Golenkov ◽  
Heinz Ludwig ◽  
Martin H Kropff ◽  
Nuriet K Khuageva ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Range ◽  
Parent Compound ◽  
Single Agent ◽  
Objective Response ◽  
Study Drug ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Duration Of Treatment

Abstract Background: Imexon (AOP 99.0001 (4-imino-1,3-diazobicyclo-(3, 1, 0)-hexan-2-one) exerts antiproliferative activity on a range of tumor cells including myeloma cells and was found to inhibit tumor development in murine models of B-cell lymphoma. The antitumor activity of Imexon is caused by a sequence of molecular events starting with alkylation of thiol groups, reduction of the intracellular antioxidative defence mechanism, increase of reactive oxygen species (ROS) in mitochondria, and mitochondrial damage and induction of apoptosis. Methods/Patients: 36 patients with relapsed or refractory myeloma who had been pretreated with at least two lines of prior therapy were included. Imexon was applied as a 15-min infusion on 5 consecutive days for 2 weeks (d1–5 and d8–12) with a rest period of one week (1 cycle). Escalation of the dose of Imexon was started with 50 mg/m2 during the phase I part of the study. Results: The plasma half life of the parent compound and its active metabolite Imexon was found to be approximately 1.2 hrs and 2.6 hrs, respectively. The mean duration of treatment with Imexon was 6.8 weeks in a dose range between 50 and 1000 mg/m2 without reaching dose limiting toxicity. Drug related grade 1–2 AEs occurring with a frequency of &gt;10 % were fatigue, nausea, constipation, headache, anorexia, muscle/bone pain, anemia, thrombocytopenia, leucopenia and transient elevation of GGT Grade 3–4 AEs related to study drug were leucopenia (n=3), anemia (n=2), thrombocytopenia (n=4), osteonecrosis (n=1), creatinine increase (n=1). In two patients dose reductions due to AEs were required. A total of 7 SAEs occured in 4 patients. All SAEs occurred at the 400 mg/m2 DL 1 SAE (increase in creatinine) was considered to be related to study drug. There was no correlation between the dose of the study drug and AEs. In addition, no mortality was encountered while patients were on treatment with Imexon. Imexon treatment resulted in a minimal response in one patient at the DL of 500 mg/m2. In addition, a significant improvement of the preexisting distal polyneuropathy was noted in this patient during these first 3 therapy cycles. After discontinuation of Imexon, reappearance of the polyneuropathy was noted within 4 months. This led to retreatment of the patient at a dose level of 600 mg/m2, which resulted in a gradual and finally complete resolution of the polyneuropathy with maintenance of the MR, but without further reduction in the mIg. No other objective response was observed in this study. Conclusion: Overall, Imexon was safe and well tolerated in the dose range investigated. Imexon demonstrated only minor clinical activity in one patient. These results do not support the further development of Imexon as single agent in multiple myeloma. Due to its unique mechanism of action and its favourable toxicity profile it may, however, qualify for use and evaluation in combination with other agents in multiple myeloma and other malignancies.

An open-label phase II study comparing two doses of MK-6482 for the treatment of advanced renal cell carcinoma (RCC) following progression on prior systemic therapy.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS369-TPS369
Author(s):  
Michael B. Atkins ◽  
Yanfang Liu ◽  
Rodolfo F. Perini ◽  
Ananya Roy ◽  
John B. A. G. Haanen
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Systemic Therapy ◽  
Objective Response ◽  
Locally Advanced ◽  
Prognostic Scores ◽  
Survival Duration ◽  
Karnofsky Performance Scale ◽  
Open Label ◽  
Prior Systemic Therapy

TPS369 Background: Treatment options for RCC in the late-line setting after immunotherapy and vascular endothelial growth factor (VEGF)-targeted therapy are limited. Hypoxia-inducible factor (HIF)-2α is a transcription factor that has been established as an oncogenic driver in clear cell RCC (ccRCC). The first-in-class small molecular HIF-2α inhibitor, MK-6482, recently showed promising antitumor activity in a cohort of heavily pretreated ccRCC patients (pts) and in pts with von Hippel-Lindau–disease-associated RCC for which the FDA granted Breakthrough Therapy Designation to MK-6482. Methods: This randomized, open-label, multicenter phase II trial will evaluate the efficacy and safety of 2 doses of MK-6482 in pts with advanced RCC who have experienced progression after prior systemic therapy (NCT04489771). Eligible pts are male or female aged ≥18 years with histologically confirmed locally advanced or metastatic ccRCC (measurable disease per RECIST v1.1) who have experienced progression after 1-3 prior systemic therapies comprising an anti-PD-1/L1 agent combined with a VEGF-targeted tyrosine kinase inhibitor (TKI) or an anti-cytotoxic T lymphocyte-associated antigen-4 agent and have undergone no more than 3 prior systemic regimens; and a Karnofsky Performance Scale ≥70. Treatment progression on anti-PD-1/L1 combination therapy was defined as pts who received at least 2 doses of anti-PD-1/L1 therapy and demonstrated radiographic disease progression as assessed by the investigator. Pts who have received prior treatment with MK-6482 or another HIF-2α inhibitor, and those requiring intermittent or chronic supplemental oxygen, or with a baseline hemoglobin less than 10 g/dL, a history of human immunodeficiency virus, hepatitis B or hepatitis C infection, or active central nervous system metastases will be excluded. Approximately 150 pts will be randomly assigned 1:1 to oral MK-6482 120 mg once daily (QD) or 200 mg QD; treatment will continue until progression, unacceptable toxicity, or withdrawal. Pts will be stratified by International Metastatic RCC Database Consortium prognostic scores (0, 1-2, 3-6) and the number of prior TKI-containing therapies (0, 1, or 2-3). Imaging with computed tomography or magnetic resonance imaging will be undertaken on Week 9 from the date of randomization, every 8 weeks through Week 49, and every 12 weeks thereafter. Adverse events will be monitored throughout the study and for 30 days after treatment (90 days for serious adverse events). The primary end point is objective response rate per RECIST v1.1 by blinded independent central review (BICR). Secondary end points are progression-free survival, duration of response and clinical benefit rate per RECIST v1.1 by BICR, overall survival, pharmacokinetics, and safety. Safety will be analyzed using a tiered approach. This study is recruiting. Clinical trial information: NCT04489771 .

Regomune: A phase II study of regorafenib + avelumab in solid tumors—Results of the biliary tract cancer (BTC) cohort.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4096-4096
Author(s):  
Sophie Cousin ◽  
Carine A. Bellera ◽  
Jean Philippe Guégan ◽  
Thibault Mazard ◽  
Carlos A. Gomez-Roca ◽  
...  
Keyword(s):  
Phase Ii ◽  
Adaptive Design ◽  
Objective Response ◽  
Locally Advanced ◽  
Survival Rates ◽  
Previous Treatment ◽  
Progression Free Survival ◽  
Treatment Interruption ◽  
Clinical Activity ◽  
Open Label

4096 Background: Regorafenib (R) has shown promising efficacy in patients (pts) with BTC refractory to standard chemotherapy. Anti-PD1/PD-L1 antibodies have only limited clinical activity. Synergy between R and anti–PD-1/PD-L1 antibodies has been shown in pre-clinical solid tumor models. Methods: This is a single-arm open-label multicentric phase II trial (Bayesian adaptive design) assessing the efficacy and safety of R (160 mg QD 3weeks/4) + avelumab (A) (10 mg/kg every 2 weeks) combination in BTC pts. The primary endpoint was the objective response rate under treatment, based on central review according to RECIST 1.1. Secondary endpoints included: 1-year progression free survival (PFS), 1-year overall survival (OS), and Safety using NCI-CTCAE v5.0. Correlative studies were planned from pts tumor samples obtained at baseline. Results: Between Nov. 2018 and Nov. 2019, 34 BTC pts were enrolled in 4 centers. Median age was 63 (range 36 – 80). Median follow-up was 9.8 months. Median number of previous treatment lines for metastatic or locally advanced disease was: 2 (range 1 – 4). Twenty-nine (85.3%) pts experienced at least 1 dose modification or treatment interruption of R or A due to an adverse event (AE) related to the treatment. The most common grade 3/4 AEs were : Hypertension (17.6%), Fatigue (14.7%), and maculo-papular rash (11.8%). No death was related to the treatment. Among the 29 pts with at least one imaging tumor assessment, 4 (13.8%) achieved a partial response, and 11 (37.9%) demonstrated stable disease including 10 (34.5%) pts with tumor shrinkage. Fourteen pts (48.3%) had progressive disease. The median PFS and OS were 2.5 months (95%CI 1.9 – 5.5) and 11.9 months (95%CI 6.2 – NA) respectively. Baseline tumor samples were available for 27 pts. High IDO and PD-L1 expression at baseline was associated with better outcome. Conclusions: The R+A combination is associated with significant anti-tumor activity with promising survival rates in this heavily pre-treated population. Full Biomarkers analyses will be presented at the meeting. Clinical trial information: NCT03475953.

A phase IIb, open-label, single-arm study of zanidatamab (ZW25) monotherapy in subjects with advanced or metastatic HER2-amplified biliary tract cancers.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS352-TPS352
Author(s):  
Shubham Pant ◽  
Michel Ducreux ◽  
James J. Harding ◽  
Milind M. Javle ◽  
Do-Youn Oh ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Biliary Tract ◽  
Single Agent ◽  
Objective Response ◽  
Receptor Internalization ◽  
Her2 Amplification ◽  
Open Label ◽  
Biliary Tract Cancers ◽  
Anti Tumor Activity

TPS352 Background: Advanced biliary tract cancers (BTCs), including gallbladder cancer (GBC) and cholangiocarcinoma (CC), have a poor prognosis. Zanidatamab (ZW25) is a novel bispecific antibody that targets HER2 domains ECD2 and ECD4, resulting in increased antibody binding density and improved receptor internalization and downregulation relative to trastuzumab. In an ongoing phase I trial (ZWI-ZW25-101; NCT02892123), single-agent zanidatamab was well tolerated and showed promising anti-tumor activity across HER2-expressing solid tumors, including BTCs. These results formed the basis for a phase IIb study of zanidatamab in patients with BTC. Methods: Study ZWI-ZW25-203 (NCT04466891) is a global, multicenter, open-label, single-arm, phase IIb trial designed to evaluate the anti-tumor activity of zanidatamab monotherapy in patients with HER2-amplified, inoperable and advanced or metastatic BTCs, including GBC and CC. Patients must have received at least 1 prior gemcitabine-containing systemic chemotherapy regimen for advanced disease and have experienced disease progression after (or developed intolerance to) their most recent prior therapy. New or archival tumor tissue is required from all patients for HER2 amplification and protein expression testing at a central lab using in situ hybridization (ISH) and immunohistochemistry (IHC) assays. Approximately 100 patients with HER2 amplification by ISH will be enrolled. Zanidatamab 20 mg/kg will be administered intravenously every 2 weeks until one of the treatment discontinuation criteria is met. The primary endpoint of the study is the confirmed objective response rate (ORR) by independent central review per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Secondary endpoints include duration of response (DOR), proportion of patients with DOR ≥ 16 weeks, disease control rate, progression-free survival, overall survival, safety, quality of life, and disease-related pain. The safety and tolerability of zanidatamab will be assessed by recording the frequency and severity of adverse events, serious adverse events, and laboratory abnormalities, as well as the frequency of zanidatamab dose modifications. The study is currently open for enrollment. Clinical trial information: NCT04466891.

A Multicentre Phase II Study of the Aminopeptidase Inhibitor, CHR- 2797, in the Treatment of Elderly and/or Previously Treated patients with Acute Myeloid Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 961-961 ◽  
Author(s):  
B. Lowenberg ◽  
F. Davies ◽  
C. Müller-Tidow ◽  
Ulrich Dührsen ◽  
A. Burnett ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Performance Status ◽  
Single Agent ◽  
Clinical Activity ◽  
Open Label ◽  
Elderly Aml ◽  
Previously Treated Patients ◽  
Previously Treated

Abstract Tosedostat (TSD, CHR-2797) is an aminopeptidase inhibitor that selectively depletes amino acid pools in malignant cells, resulting in anti-proliferative, pro-apoptotic and antiangiogenic effects. In a phase I study, treatment with TSD resulted in complete remission in a number of refractory AML patients. The primary objective of this phase II study was to determine whether TSD was a sufficiently effective therapy to warrant pivotal studies. Methods. This was an open label, single agent, phase II study to assess clinical activity of TSD in elderly and/or previously treated patients with AML/MDS. Patients were treated with once daily oral doses of the maximum acceptable dose (130 mg) of TSD for up to 84 days. Further treatment was allowed if, in the opinion of the investigator, this was considered to be beneficial. Clinical responses were assessed by monthly bone marrow aspirates and weekly hematological assessments. Results. Of the 41 TSD-treated patients with AML (n=38) or MDS (n=3), who were enrolled between March and October 2007, 27 were male, 14 female, with a mean age of 67 years (range 34–82). The median performance status (ECOG) at baseline was 1 (range 0–2). Twelve (31.6%) AML patients and 2 (66.7%) MDS patients were chemotherapy naïve, and 9 (23.7%) AML patients had either secondary disease or adverse cytogenetics. For 16 (39%) patients, treatment with TSD was a second or later salvage attempt. Thirty two patients (30 AML, 2 MDS-RAEB1 and 2) received ≥28 days treatment, and 21 (51.2%) patients completed the formal 84-day study period (19 AML, 2 MDS). Nine (22%) of the patients (7 AML, 2 MDS) continued treatment with TSD after 84 days, and 6 (15%) patients were on TSD in total for more than 6 months (4 AML, 2 MDS). Ten (26.3%) of the AML patients responded to treatment; amongst these, 2 patients received TSD as 2nd/3rd salvage therapy, and a further 2 patients did not show a complete response (CR) after 2 previous induction courses of chemotherapy. Three AML patients achieved a CR (< 5% blasts in bone marrow), of whom 2 were in durable remission (232 days, continuing*; 171 days), and 7 had a partial response (PR, 5–15% blasts) lasting approximately 1–3 months. Two (66.7%) of the MDS patients also responded to treatment with TSD; these patients maintained stable disease for more than 6 months. All responders (CR, PR and SD) were >60 years at the time of the first dose. Median overall survival in AML patients was 130 days (range 8 – 478 days*). The most frequently reported adverse events were: fatigue (61%), thrombocytopenia (49%), pyrexia (39%), peripheral edema (39%) and diarrhea (34%); 9 (22%) patients withdrew due to drug related toxicity. TSD had no effect on hemoglobin or neutrophils. Conclusions. This study in patients with advanced AML/MDS with adverse prognosis demonstrates the anti-leukemic activity of TSD in elderly AML patients, as measured by CR and decreases in leukemic blasts. In addition, 2 relapsed high risk MDS patients achieved disease stabilization. TSD at 130mg qd is also very well tolerated over a long period of exposure (6–10 months). These results support further pivotal studies with TSD in elderly AML and MDS patients.

Phase 1 Study of Anti-CD22 Immunoconjugate Inotuzumab Ozogamicin (CMC-544) Plus Rituximab In Japanese Patients with Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2872-2872 ◽  
Author(s):  
Kiyohiko Hatake ◽  
Michinori Ogura ◽  
Kiyoshi Ando ◽  
Kota Tokushige ◽  
Chiho Ono ◽  
...  
Keyword(s):  
Adverse Events ◽  
B Cell ◽  
Malt Lymphoma ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Study Drug ◽  
B Cell Lymphoma ◽  
Japanese Patients ◽  
Clinical Activity ◽  
Inotuzumab Ozogamicin

Abstract Abstract 2872 Background: Inotuzumab ozogamicin (CMC-544) is a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. Inotuzumab ozogamicin targets CD22, which is expressed in the majority of B-cell non-Hodgkin lymphomas (NHL). The maximum tolerated dose of inotuzumab ozogamicin administered as a single agent was previously determined to be 1.8 mg/m2 administered intravenously every 28 days, and clinical activity was shown in both non-Japanese and Japanese patients with relapsed or refractory B-cell NHL. Safety and efficacy data in non-Japanese patients with relapsed or refractory B-cell NHL treated with inotuzumab ozogamicin given in combination with rituximab was previously reported. Objectives: To assess safety, pharmacokinetics, and preliminary efficacy of inotuzumab ozogamicin in combination with rituximab in Japanese patients with relapsed or refractory B-cell NHL. Methods: Patients were eligible if they had both CD20 and CD22-positive B-cell NHL, which had not responded to or progressed after 1 or 2 therapies. At least 1 prior regimen had to contain rituximab, and patients could not have progressed under treatment or within 6 months of start of rituximab-containing therapy. Patients received 375 mg/m2 of rituximab on Day 1 followed by 1.8 mg/m2 of inotuzumab ozogamicin on Day 2 of each 28-day cycle for up to 8 cycles, provided that there was no disease progression or intolerable toxicity. Adverse events (AEs) were reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 3.0 in patients who received at least 1 dose of the study drug. Objective response rate (ORR) was evaluated according to the International Response Criteria for NHL. Results: Ten patients were enrolled and treated with 1.8 mg/m2 of inotuzumab ozogamicin in combination with rituximab for a median of 4 cycles. Median age was 60.5 (range 46 – 74), 50% were male, and 50% each had 1 and 2 prior chemotherapy regimens. Six patients were diagnosed as having follicular lymphoma (FL), 2 patients as mantle cell lymphoma (MCL), 1 patient each as diffuse large B-cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue (MALT) lymphoma. Grade 3 or 4 treatment-emergent AEs reported in >20% of the patients were thrombocytopenia (70%), neutropenia (50%), leukopenia (30%), and lymphopenia (30%). AEs resulting in treatment discontinuation were neutropenia (30%) and hyperbilirubinemia (20%). No serious AEs were observed. An ORR of 80% (95% CI, 44 – 98%) was observed in the 10 patients treated. Five out of 6 patients with FL and 1 patient with MALT lymphoma achieved a complete response (CR). One out of 2 patients with MCL achieved unconfirmed CR (CRu), and 1 patient with FL attained partial response (PR). Progression-free survival (PFS) rate at 52 weeks was estimated to be 89% (95% CI, 43 – 98). ORR was 88% (95% CI, 47 – 100%) in the 8 patients that received at least 2 doses of the study drug and had at least 1 post-baseline tumor assessment (5 FL, 2 MCL, and 1 MALT lymphoma). Results of the pharmacokinetics assessment will be presented at the meeting. Conclusion: The combination of inotuzumab ozogamicin plus rituximab has a safety profile similar to that previously reported for inotuzumab ozogamicin as a single agent, with hematologic AEs being the most frequent toxicities. The preliminary but encouraging evidence of clinical activity in Japanese patients with relapsed or refractory B-cell NHL warrants continued clinical development of this combination. Disclosures: Tokushige: Pfizer Japan Inc.: Employment. Ono:Pfizer Japan Inc.: Employment. Vandendries:Pfizer Inc.: Employment, Equity Ownership.

Phase II Study of the Histone Deacetylase Inhibitor Panabinostat (LBH589) in Patients with Low or Intermediate-1 Risk Myelodysplastic syndrome

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1731-1731
Author(s):  
Sophie Dimicoli ◽  
Elias Jabbour ◽  
Gautam Borthakur ◽  
Tapan Kadia ◽  
Zeev Estrov ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Median Duration ◽  
Lower Risk ◽  
Response Rate ◽  
Phase Ii Study ◽  
Single Agent ◽  
Clinical Activity ◽  
Number Of Patients ◽  
Deacetylase Inhibitor

Abstract Abstract 1731 Panabinostat is a very potent panhistone deacetylase inhibitor (HDACi) with activity in acute myelogenous leukemia (CCR 2006;12: 4628). We hypothesized that single agent panabinostat could be active in patients with low and intermediate-1 risk MDS. Oral route of administration and safety profile further increased interest in this approach. To test this concept we designed a phase II study of panabinostat for patients above 18 years of age with lower risk disease. Patients could have received prior therapy or be treatment naïve. Appropriate renal, hepatic and cardiac functions were required. Patients were excluded if they had previous HDACi treatment. Patients with history of cardiac pathology such as rhythm alterations were excluded from the study. Use of drugs that could induce QT prolongation and CYP3A4 inhibitors were not allowed. Panabinostat was used at dose of 20 mg orally three times a week for consecutive 3 weeks with cycles repeated every 4 weeks. The primary objective of the study was overall response rate defined by IWG. A maximum of 40 patients could be enrolled. The study was to stop early if the expected response rate was less than 15%. Stopping rules were as follows: Stop if the number of patients with hematologic improvement/the number of patients evaluated was 0/15 or 1/32. The study also contained a stopping rule for non-hematological toxicity. Thirteen patients were enrolled between August 2009 and December 2010. Median age was 70 years (range 47 to 84, 84% of patients older than 60), 70% were transfusion dependent, 70% had intermediate-1 risk MDS, most patients were diploid but one patient with del(5q), one with trisomy 8, one with complex cytogenetics and 2 with deletion of 20q were included. Median percent of marrow blasts was 1% (range 1 to 6%). At start of therapy, median hemoglobin was 9.5 (range 7.5–11.2 G/dL), median platelet count was 56 (range 6–431 k/uL) and median white blood cell count was 4.6 (range 0.8–20.3 k/uL). Approximately 40% had previous therapy for MDS including hypomethylating agents, lenalidomide and investigational agent. Median number of prior therapies for treated patients was 2 (range 1 to 4). Median duration of disease at time of enrollment was 10 months (range 1–50). Patients received a median of 4 cycles of panabinostat (range 1–9). Of 13 patients, 1(8%) achieved a hematological improvement including both an erythroid and platelet response that lasted for 3 months. No complete remissions or partial responses were documented. Six patients (46%) had stable disease for a median duration of 6 months (range 2–13.6). Median overall survival was 15 months (1–31 months). Two patients died because progression to AML. Therapy was well tolerated: no major adverse events were documented except for one patient that developed significant QTc prolongation. Adverse events included mild fatigue and gastrointestinal toxicity. As a biomarker of molecular activity, histone H3 acetylation was measured in 5 patients with variable results. Induction of acetylation was documented in 2. Despite the fact that the stopping rule for activity was not officially met, because of the very modest clinical activity observed, the study was closed to new patient entry. In conclusion, panabinostat given as a single agent orally at a dose of 20 mg thee times a week for 3 weeks followed by one week of rest has limited clinical activity in patients with lower risk MDS. Disclosures: No relevant conflicts of interest to declare.

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