A phase I study of simvastatin in combination with topotecan and cyclophosphamide in pediatric patients with relapsed and/or refractory solid and CNS tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10541-10541
Author(s):  
Thomas Cash ◽  
Hunter C. Jonus ◽  
Maya Tsvetkova ◽  
Jan Hendrik Beumer ◽  
Jasmine Y Lee ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Wilms Tumor ◽  
Phase 1 ◽  
Cns Tumors ◽  
Study Patient ◽  
Hematologic Toxicity ◽  
Malignant Rhabdoid Tumor ◽  
Critical Pathway ◽  
Peripheral Blood Mononuclear ◽  
Grade 3

10541 Background: HMG-CoA reductase inhibitors (statins) can inhibit IL-6-mediated STAT3 activation, a critical pathway in pediatric CNS and solid tumors. Statins also inhibit tumor proliferation, angiogenesis, and restore apoptosis in preclinical pediatric solid tumor models. We therefore conducted a phase 1 trial of simvastatin in combination with topotecan and cyclophosphamide in children with relapsed/refractory (r/r) solid and CNS tumors. Methods: Eligible patients were 1-29 years of age with a r/r solid or CNS tumor. Simvastatin was administered orally twice daily on days 1-21, with topotecan 0.75 mg/m2/dose IV and cyclophosphamide 250 mg/m2/dose IV on days 1-5. Four dose levels (DLs) were planned: 140, 180, 225, 290 mg/m2/dose. A 3+3 design was used to determine the maximum tolerated dose (MTD). Pharmacokinetic and pharmacodynamic analyses were performed. Results: The median (range) age of 14 eligible patients was 11.5 years (1 - 23). Diagnoses included neuroblastoma (N = 4), sarcoma (N = 7), and one each of malignant rhabdoid tumor of kidney, medulloblastoma, and Wilms tumor. Eleven DLT-evaluable patients received a median of 4 cycles (range: 1-6). There were 3 cycle 1 DLTs, grade 3 diarrhea and grade 4 creatine phosphokinase (CPK) increased at DL 1, and grade 4 CPK increased at DL 0 (100 mg/m2/dose). Grade 3/4 treatment-related cycle 1 adverse events occurring in ≥ 10% patients were neutropenia (100%), leukopenia (100%), thrombocytopenia (91%), lymphopenia (91%), anemia (55%), febrile neutropenia (55%) and CPK increased (18%). Best overall response was partial response in 1 patient and stable disease in four. Simvastatin and simvastatin acid Cmax (geomean 82.5 and 12.6 ng/mL) and AUC0-6 (geomean 82.5 and 12.6 ng•h/mL) were comparable with reported pediatric literature values (Cmax 3.5 and 0.4-2.1 ng/mL; AUC0-8 10.7 and 3.8 ng•h/mL) after correction for the higher doses (3.77 vs 0.16 mg/kg) used in our study. Patient peripheral blood mononuclear cells showed maximum phospho-(p)STAT3 inhibition on Day 5, with recurrence by Day 21 despite continued simvastatin dosing. Plasma IL6 levels showed sustained IL6 inhibition with decrease to normal values by Day 21 in all patients, indicating potential on target effects. Conclusions: For this first-in-pediatrics trial of statins as anti-cancer therapy, the MTD of simvastatin with chemotherapy was 100 mg/m2/dose. This combination was well-tolerated with predominantly hematologic toxicity and predictable DLTs related to simvastatin. Clinical trial information: NCT02390843.

Effect of vorinostat (VOR) and hydroxychloroquine (HCQ) on immunity and autophagy in metastatic colorectal cancer (mCRC).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 670-670
Author(s):  
Sukeshi R. Patel ◽  
Vincent Hurez ◽  
Steffan T Nawrocki ◽  
Martin Goros ◽  
Joel Michalek ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Immunity ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Peripheral Blood Mononuclear ◽  
Lysosomal Protease ◽  
Grade 5 ◽  
Grade 3 ◽  
Expansion Cohort

670 Background:HCQ enhances the anti-cancer activity of the histone deacetylase inhibitor, VOR in pre-clinical CRC models. Our phase 1 dose escalation trial found that patients (pts) with mCRC obtained prolonged clinical benefit from VOR + HCQ. Thus, a single arm expansion cohort in refractory mCRC was done. Methods: Pts with refractory mCRC received VOR 600 mg by mouth (PO) + HCQ 400 mg PO daily, in a 3-week cycle. The primary endpoint was median progression-free survival (mPFS). Secondary endpoints: median overall survival (mOS), adverse events (AE) (NCI-CTCAEv3.0), flow cytometry (FACS) of peripheral blood mononuclear cells (PBMCs), tumor biopsies. Results: 20 pts were enrolled (19 evaluable for survival): mean age 61 (44-74). Female 7/male 23, 9 Caucasian/10 Hispanic/1 Black, 11 KRAS mutated. ECOG 0-1 (18 pts). 3+ prior lines (13), previous regorafenib (4). Dose level reduction on study (7). mPFS 2.8 months (95% CI: 1.63-8.16). mOS 6.7 months (95% CI: 4.63-NR). Treatment-related grade 3 AEs: nausea/vomiting (3), anemia (3). Grade 4 thrombocytopenia (3). Grade 4 INR elevation (1 pt on Coumadin). No grade 5 AEs. Five pts (26%) had stable disease ≥12 weeks. Treatment significantly reduced regulatory and PD-1+ (exhausted) CD4+ and CD8+ T cells and increased CD45RO+CD62L-CD4+ (effector) T cells, consistent with improved anti-tumor immunity. On-study biopsies (3) showed increased lysosomal protease CTSD and LC3-II consistent with autophagy inhibition. Conclusions: VOR/HCQ is active, safe and tolerated in refractory CRC patients, resulting in potentially improved anti-tumor immunity (decreased exhausted and regulatory T cells and increased effector phenotype T cells) and reduced tumor autophagy. A randomized phase II trial of VOR/HCQ versus regorafenib is now open. Clinical trial information: NCT01023737.

scholarly journals EPCT-02. PBTC-051: FIRST IN PEDIATRICS PHASE 1 STUDY OF CD40 AGONISTIC MONOCLONAL ANTIBODY APX005M IN PEDIATRIC SUBJECTS WITH RECURRENT/REFRACTORY BRAIN TUMORS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii304-iii304
Author(s):  
Holly Lindsay ◽  
Arzu Onar-Thomas ◽  
Mehmet Kocak ◽  
Tina Young Poussaint ◽  
Girish Dhall ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Dose Level ◽  
Pediatric Patients ◽  
Phase 1 ◽  
Pediatric Brain Tumor ◽  
Cns Tumors ◽  
Level 3 ◽  
Grade 3 ◽  
Expansion Cohort ◽  
Antigen Presenting

Abstract BACKGROUND CD40 is a co-stimulatory molecule expressed on antigen presenting cells (APCs). APX005M is a CD40 agonist monoclonal antibody which stimulates innate and adaptive anti-tumor immunity through activation of APCs, macrophages, and antigen-specific CD8+T-cells. Pediatric Brain Tumor Consortium study PBTC-051 is the first investigation of APX005M in pediatric patients and is evaluating the safety, recommended phase 2 dose (RP2D), pharmacokinetics, and preliminary efficacy of APX005M in children with central nervous system (CNS) tumors. RESULTS Accrual of patients with recurrent/refractory primary malignant CNS tumors (stratum 1) began in March 2018. 16 patients (2 ineligible) have enrolled on this stratum; 14 were treated. Dose escalation through 3 planned dose levels of APX005M was completed without excessive or unanticipated toxicities. The highest dose level (0.6 mg/kg q3 weeks) is the presumptive RP2D, and an expansion cohort is currently enrolling at this dose. 2 patients at dose level 3 have received >12 cycles of therapy. Grade 3 or higher adverse events at least possibly attributable to APX005M include 11 lymphopenia, 5 neutropenia, 5 leukopenia, 3 ALT elevations, 1 AST elevation, 1 thrombocytopenia, and 1 hypoalbuminemia. PK data will be available March 2020. Stratum 2 is now enrolling patients with post-radiation/pre-progression DIPG beginning at dose level 2, with 1 patient currently enrolled. CONCLUSION The CD40 agonistic antibody APX005M has demonstrated preliminary safety in pediatric patients with recurrent/refractory primary malignant CNS tumors and has a likely RP2D of 0.6 mg/kg q3 weeks in this population. Preliminary efficacy data are pending.

Phase 1/2 study of eprenetapopt (APR-246) in combination with pembrolizumab in patients with solid tumor malignancies.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3161-TPS3161
Author(s):  
Ecaterina Elena Dumbrava ◽  
Amit Mahipal ◽  
Xin Gao ◽  
Geoffrey Shapiro ◽  
Jason S. Starr ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Tumor Growth Inhibition ◽  
Advanced Solid Tumors ◽  
Peripheral Blood Mononuclear

TPS3161 Background: The p53 pathway has been implicated in antitumor immunity, including antigen presentation and T-cell proliferation. Loss of p53 function can increase resistance to immunotherapy across many tumor types. Eprenetapopt (eprenet) is a small molecule that stabilizes the folded structure of p53, resulting in activation of mutant p53 and stabilization of wild-type (WT) p53. It also targets the cellular redox homeostasis, resulting in induction of apoptosis in tumor cells. In vivo, mice carrying supernumerary copies of the TP53 gene harbor a pro-inflammatory tumor microenvironment, an effect recapitulated in TP53 normal-copy mice treated with eprenetapopt. Combining eprenetapopt and anti-PD1 or anti-CTLA4 therapy resulted in enhanced tumor growth inhibition and improved survival in TP53 WT mice inoculated with B16 melanoma and MC38 colon adenocarcinoma cells . Based on these results, we hypothesized that eprenet-induced p53 stabilization may augment response to immunotherapy. To test this hypothesis, we are conducting a phase 1b/2 study of eprenet in combination with pembrolizumab (eprenet+pembro) in pts with solid tumors. Methods: The primary objectives are to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) and to assess the safety and tolerability of eprenet+pembro in pts with advanced solid tumors. The secondary objectives are to estimate the anti-tumor activity and to describe the pharmacokinetics of the combination. Exploratory objectives include assessing predictive and pharmacodynamic markers of response. The study includes a safety lead-in with a 3+3 dose de-escalation design for pts with advanced solid tumors with known tumor TP53 mutation status ( TP53 WT is acceptable) (max 18 pts), followed by expansion cohorts in pts with NSCLC, gastric/GEJ and urothelial cancer (max 100 pts). In expansion, pts with urothelial and gastric cancers must be naïve to anti-PD-1/ L1 therapy. Eprenet is given IV once daily on Days 1–4 while pembro is administered on Day 3 of each 21-day cycle. The RP2D of eprenet+pembro is considered the dose at which ≤ 1 of 6 pts in a cohort has a dose-limiting toxicity (DLT). Primary endpoints are occurrence of DLTs, adverse events (AEs) and serious AEs with eprenet+pembro. Key secondary endpoints are best objective response, progression free survival and overall survival. Exploratory endpoints include gene mutations by next generation sequencing (including TP53), mRNA expression, multiplex immunohistochemistry and transcriptomics, multiplex flow cytometry on peripheral blood mononuclear cells and cytokines in serum. Continuous monitoring of toxicity will be conducted. The trial opened in May 2020 and is actively enrolling patients. Clinical trial information: NCT04383938.

scholarly journals Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL

Blood ◽  
2019 ◽  
Vol 134 (11) ◽  
pp. 851-859 ◽  
Author(s):  
Constantine S. Tam ◽  
Judith Trotman ◽  
Stephen Opat ◽  
Jan A. Burger ◽  
Gavin Cull ◽  
...  
Keyword(s):  
B Cell ◽  
Dose Escalation ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Lymphocytic Leukemia ◽  
B Cell Malignancies ◽  
Phase 1 Study ◽  
End Points ◽  
Once Daily ◽  
Grade 3

Abstract Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 + 3 dose escalation) had relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The primary end points were safety and tolerability, and definition of the maximum tolerated dose (part 1). Additional end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. Reported herein are results from 144 patients enrolled in the dose-finding and CLL/SLL cohorts. No dose-limiting toxicities occurred in dose escalation. Median BTK occupancy in peripheral blood mononuclear cells was >95% at all doses. Sustained complete (>95%) BTK occupancy in lymph node biopsy specimens was more frequent with 160 mg twice daily than 320 mg once daily (89% vs 50%; P = .0342). Consequently, 160 mg twice daily was selected for further investigation. With median follow-up of 13.7 months (range, 0.4-30.5 months), 89 CLL/SLL patients (94.7%) remain on study. Most toxicities were grade 1/2; neutropenia was the only grade 3/4 toxicity observed in >2 patients. One patient experienced a grade 3 subcutaneous hemorrhage. Among 78 efficacy-evaluable CLL/SLL patients, the overall response rate was 96.2% (95% confidence interval, 89.2-99.2). Estimated progression-free survival at 12 months was 100%. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02343120.

Safety, Tolerability, and Pharmacology of Bortezomib in Cancer Patients with Renal Failure Requiring Dialysis: Results from a Prospective Phase 1 Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3477-3477 ◽  
Author(s):  
Daniel Mulkerin ◽  
Scot Remick ◽  
Chris Takimoto ◽  
Percy Ivy ◽  
Michael Karol ◽  
...  
Keyword(s):  
Renal Impairment ◽  
Dose Escalation ◽  
Severe Renal Impairment ◽  
Phase 1 ◽  
Case Series ◽  
Sensory Neuropathy ◽  
Red Blood Cell Transfusion ◽  
Hematologic Toxicity ◽  
Severe Impairment ◽  
Grade 3

Abstract Background: Bortezomib (btz; VELCADE®) is a specific, reversible proteasome inhibitor approved for the treatment of patients (pts) with multiple myeloma (MM) and mantle cell lymphoma following at least one prior therapy. Retrospective analyses of phase 2/3 studies and case series have shown btz alone or in combination is active and tolerable in MM pts with various degrees of renal impairment, including pts on dialysis. We previously reported clinical and pharmacologic data from the first prospective, dose-escalating study of btz in adult cancer pts with various degrees of renal impairment (ASCO 2006, abstract 2032). Here we present updated safety and tolerability data for dialysis-dependent patients. Methods: Pts with advanced cancer were stratified by renal function into controls and four groups ranging from mild impairment to dialysis dependence. Pts received btz on d 1, 4, 8, and 11 of a 21-day cycle; dose escalation (0.7, 1.0, 1.3 mg/m2) proceeded in cohorts of 3 pts based on dose limiting toxicities (DLTs) observed in cycle 1. Blood samples were taken on d 1 and 8 of cycle 1 for pharmacokinetic (PK) and pharmacodynamic (PD) analysis. Adverse events (AEs) were evaluated using NCI CTC v2.0. DLTs were grade 4 neutropenia for ≥7 d or neutropenic fever, grade 4 thrombocytopenia for ≥7 d, grade 4 hemoglobin for ≥7 d, and grade ≥3 non-hematologic toxicity. Results: To date, 59 pts have been treated, including 16 controls, 34 pts with mild-to-severe impairment, and 9 dialysis pts. Among dialysis pts: 3 were treated at 0.7, 2 at 1.0, and 4 at 1.3 mg/m2; median age was 62 y (range: 42–74); tumor types were MM (n=4), follicular lymphoma (n=1), and solid tumors (n=4). Median number of treatment cycles received was 2 in controls and across renal impairment groups. Dialysis pts received a median of 2 treatment cycles (range: 1–4); 1 pt remains on therapy. Dose escalation was well tolerated, with no DLTs, in pts with mild-to-severe renal impairment. There were no DLTs in cycle 1 in dialysis pts. Toxicities were generally mild in all groups. Among dialysis pts, no unexpected toxicities were seen. One grade 4 treatment-related AE (elevated creatinine) has been reported; grade 3 treatment-related AEs include platelets/thrombocytopenia (3 pts), diarrhea, hemoglobin, leukopenia, lymphopenia, packed red blood cell transfusion, sensory neuropathy, and vomiting (1 pt each). The overall AE profile in dialysis pts was similar to that in controls and in pts with mild-to-severe impairment, although renal and metabolic AEs appeared more common in dialysis pts. Conclusions: Btz at doses up to 1.3 mg/m2 on this schedule was well tolerated in pts with advanced malignancies with mild-to-severe renal impairment and dialysis dependence. PK and PD analyses for dialysis pts treated at 1.3 mg/m2 will be reported. Btz is a viable treatment option for pts requiring dialysis.

Gemtuzumab Ozogamicin In Combination With Vorinostat and Azacitidine In Older Patients With Relapsed Or Refractory Acute Myeloid Leukemia (AML): Final Results From A Phase 1/2 Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3936-3936 ◽  
Author(s):  
Roland B. Walter ◽  
Bruno C. Medeiros ◽  
Kelda M. Gardner ◽  
Kaysey F. Orlowski ◽  
Leonel Gallegos ◽  
...  
Keyword(s):  
Research Funding ◽  
Blood Count ◽  
Treatment Initiation ◽  
Phase 1 ◽  
Gemtuzumab Ozogamicin ◽  
Hematologic Toxicity ◽  
First Relapse ◽  
Grade 3 ◽  
Refractory Aml ◽  
Count Recovery

Abstract Background Epigenetic therapeutics such as the histone deacetylase (HDAC) inhibitor, vorinostat, and the DNA methyltransferase (DNMT) I inhibitor, azacitidine, sensitize AML cells in vitro to the CD33-targeting immunoconjugate, gemtuzumab ozogamicin (GO). This observation, together with the improved clinical activity when HDAC inhibitors are used with DNMT inhibitors, prompted a phase 1/2 study (NCT00895934) of GO with vorinostat and azacitidine for primary refractory AML or AML in first relapse (remission duration ≤12 months) requiring 1stsalvage therapy. Methods Patients aged ≥50 years were eligible if they had an ECOG performance status of 0-3 and had adequate organ function. Patients with prior hematopoietic stem cell transplantation (HCT) were eligible if relapse occurred 6-12 months post-transplant. Excluded were patients with a second active malignancy, prior treatment with any of the study drugs, or central nervous system disease. Hydroxyurea was given to reduce the total white blood cell count to <25,000/μL before treatment. If there was persistent leukemia on day 15, the first cycle was repeated, and patients came off study if, after repetition, there was disease progression. In all other patients, a second cycle was begun if peripheral blood counts had recovered (blood count recovery was not required for patients with persistent leukemia) and all toxicities had resolved to ≤grade 2. Patients came off study if a partial remission was not achieved by the end of cycle 3, or if a complete remission (CR) or CR with incomplete peripheral blood count recovery (CRi) was not achieved by the end of cycle 6. During phase 1, patients were assigned to therapy according to a “3+3” study design; dose-limiting toxicity (DLT) was defined as: 1) any grade 3 non-hematologic toxicity lasting >48 hours that results in >7 day delay of the subsequent treatment cycle, with the exception of febrile neutropenia or infection; 2) any grade ≥4 non-hematologic toxicity, with the exception of febrile neutropenia/infection or constitutional symptoms if recovery to grade ≤2 within 14 days; and 3) prolonged myelosuppression (platelet count <20,000/μL and/or absolute neutrophil count <500/μL at day 42 after treatment in patients without evidence of persistent leukemia). During phase 2, a Simon minimax two-stage design was to monitor whether a response rate of 0.34 was reached, with type I and II errors set at 0.1 and assuming a historical CR rate of 17% in these patients. Results 52 eligible patients, median age 64.8 (range, 50.2-78.9) years, with either primary refractory disease (n=29) or first relapse (n=23; median duration of first CR: 3 months) were enrolled and received a median of 2 (range, 1-4) cycles of therapy. During dose escalation, 1 DLT (death due to sepsis and respiratory failure) occurred at the 4th tested dose level after cycle 1, identifying vorinostat (400 mg/day orally from days 1-9), azacitidine (75 mg/m2/day IV or SC from days 1-7), and GO (3 mg/m2/day IV on days 4 and 8) as the maximum tolerated dose (MTD). A total of 43 patients received therapy at the MTD level. Ten of these achieved CR, while 8 achieved CRi, for a CR/CRi rate of 18/43 (41.9%; exact 95% CI: 27.0-57.9%). Thirteen of the 18 patients that achieved CR/CRi were taken off protocol to receive additional, more intensive consolidative chemotherapy, including HCT (n=12). Of these 18 patients, 5 relapsed after a median of 122 (38-146) days, while 3 died while in remission after a CR duration of 46, 97, and 130 days, and 10 are in ongoing remission after a median of 326 (68- 710) days, respectively. Median overall survival for the 18 patients achieving CR/CRi was significantly longer than for those 21 patients who failed therapy but lived at least 29 days (i.e. did not experience treatment-related mortality) after treatment initiation (224.5 [range 70-798]) vs. 95 [36-900] days, log rank P-value=0.0023). Four patients died within 28 days of treatment initiation. Besides grade 3-4 cytopenias, infectious complications were the most common grade 33 adverse events. Only 1 patient developed possible liver toxicity (abdominal pain/distention and mild ascites) after 4 cycles of therapy, although bilirubin and transaminases were only minimally elevated and doppler studies were unremarkable. Conclusion Our study indicates that GO in combination with vorinostat and azacitidine has encouraging anti-AML activity in older adults with relapsed/refractory AML. Disclosures: Walter: Amgen, Inc: Research Funding; Seattle Genetics, Inc: Consultancy, Research Funding. Off Label Use: Use of vorinostat/azacitidine/gemtuzumab ozogamicin for the treatment of relapsed/refractory AML.

A Phase 1/2 Study of G-CSF, Cladribine, Cytarabine, and Dose-Escalated Mitoxantrone (G-CLAM) in Adults with Newly Diagnosed Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1068-1068 ◽  
Author(s):  
Anna B. Halpern ◽  
Megan Othus ◽  
Emily M Huebner ◽  
Kaysey F. Orlowski ◽  
Bart L. Scott ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Research Funding ◽  
Phase 1 ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Grade 3 ◽  
Dose Levels

Abstract Introduction:"7+3" with standard doses of cytarabine and an anthracycline has remained the mainstay of induction chemotherapy for newly diagnosed AML. Since some studies have shown improved outcomes with high-dose cytarabine, cladribine, or escalated doses of anthracyclines, we conducted a phase 1/2 study (NCT02044796) of G-CLAM using escalated doses of mitoxantrone for newly diagnosed AML or high-risk MDS (>10% blasts). Methods: Patients≥18 years were eligible if they had treatment-related mortality (TRM) scores of ≤6.9 (corresponding to a predicted risk of early death with standard induction chemotherapy of ≤6.9%) and adequate organ function (LVEF ≥45%, creatinine ≤2.0 mg/dL, bilirubin ≤2.5 times upper limit of normal). Excluded were patients with uncontrolled infection or concomitant illness with expected survival <1 year. In phase 1, cohorts of 6-12 patients were assigned to 1 of 4 total dose levels of mitoxantrone (12, 14, 16, or 18 mg/m2/day, days 1-3, compared to 10 mg/m2/day used in standard dose G-CLAM previously established in relapsed/refractory AML). Other drug doses were G-CSF 300 or 480 μg/day (for weight </≥76 kg; days 0-5), cladribine 5 mg/m2/day (days 1-5), and cytarabine 2 g/m2/day (days 1-5). In phase 2, patients were treated at the maximum tolerated dose (MTD) of mitoxantrone. A second identical course of G-CLAM was given if complete remission (CR) was not achieved with cycle 1. Up to 4 cycles of consolidation with G-CLA (mitoxantrone omitted) were allowed if CR or CR with incomplete platelet or blood count recovery (CRp/i) was achieved with 1-2 cycles of induction therapy. Dose-limiting toxicities (DLTs) were: 1) grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7-day delay of the subsequent treatment cycle; 2) grade ≥4 non-hematologic toxicity if recovery to grade ≤2 within 14 days, both excluding febrile neutropenia, infection or constitutional symptoms. Results: Among 33 patients (median age of 57.3 [range: 26-77], median TRM score 2.31 [0.16-5.90]) treated in phase 1, one DLT occurred at dose levels 3 and 4 (respiratory failure in both cases), establishing G-CLAM with mitoxantrone at 18 mg/m2/day as the MTD. Sixty-two patients, including 6 treated in phase 1, received G-CLAM at MTD. Patient characteristics were as follows: median age 58 (21-81) years, median TRM score 2.85 (0.06-6.73), with AML (n=52) or high-risk MDS (n=10). Cytogenetics were favorable in 6, intermediate in 44, and adverse in 12 (MRC criteria); 11 patients had NPM1 and 6 had FLT3 mutations. Fifty-two patients (83.9%, 95% confidence interval: 72.3-92.0%) achieved a CR (n=48 [77.4%: 65.0-87.1%]), or CRp/i (n=4 [6.5%: 1.8-15.7%]) with 1-2 cycles of therapy. Only 3 patients required 2 cycles to best response. Among the 48 CR patients, 43 (89.6%) were negative for measurable residual disease (MRDneg) by flow cytometry. Four patients had morphologic leukemia free state, 1 patient with myeloid sarcoma had a partial remission, 4 had resistant disease, and 1 died from indeterminate cause. One patient died within 28 days of treatment initiation (septic shock). Median times to an absolute neutrophil count ≥500/μL and a platelet count of ≥50,000/μL were 26 and 23 days. Besides infections and neutropenic fever, maculopapular rash, and hypoxia (fluid overload/infection-related) were the most common grade ≥3 adverse events. In addition to the phase 1/2 MTD cohort, there were 15 patients treated in an expansion cohort and 3 eligible patients treated off protocol with mitoxantrone at 18 mg/m2. For these 80 patients combined treated at MTD, the CR and CR/CRp/i rates were 76.3% and 81.2%. After multivariable adjustment, compared to 300 patients treated with 7+3 on the SWOG S0106 trial, G-CLAM with mitoxantrone 18mg/ m2 was associated with an increased probability of CR (odds ratio [OR]= 3.08, p=.02), CR/CRp/i (OR=2.96, p=.03), a trend towards improved MRDnegCR (OR= 3.70, p=.06), and a trend towards improved overall survival ([OS]; hazard ratio=0.34, p=.07). For the entire study cohort, the 6 and 12-month relapse-free survival were 73% (64-83%) and 62% (42-74%) and the 6 and 12-month OS were 89% (82- 96%) and 77% (67-88%). Conclusions: G-CLAM with mitoxantrone up to 18 mg/m2/day is well tolerated and has potent anti-leukemia activity. This regimen may warrant further randomized comparison with 7+3. We also plan to examine the addition of sorafenib to G-CLAM in newly diagnosed AML patients regardless of FLT3 status. Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Scott:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees. Becker:GlycoMimetics: Research Funding. Erba:Ariad: Consultancy; Gylcomimetics: Other: DSMB; Pfizer: Consultancy; Sunesis: Consultancy; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Novartis: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Speakers Bureau; Agios: Research Funding; Astellas: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celator: Research Funding; Seattle Genetics: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Amgen: Consultancy, Research Funding.

Phase I trial of the oral histone deacetylase inhibitor MS-275 administered with food

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13036-13036 ◽  
Author(s):  
E. A. Donovan ◽  
A. Sparreboom ◽  
W. Figg ◽  
J. Trepel ◽  
K. Maynard ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Mononuclear Cells ◽  
Interindividual Variability ◽  
Protein Acetylation ◽  
Hdac Inhibition ◽  
Peripheral Blood Mononuclear ◽  
Advanced Malignancy ◽  
Grade 3

13036 Background: The histone deacetylase (HDAC) inhibitor MS-275, a synthetic benzamide derivative, has demonstrated antitumor activity in vitro & in vivo. After determining maximum tolerable dose (MTD = 2 mg/m2) & dose limiting toxicity (DLT) for MS-275 given to fasting patients (pts) weekly ×4 q6 weeks, we explored toxicity profile, MTD, & pharmacokinetics (PK) of MS-275 when given po on the same schedule with food. Methods: MS-275 at 2, 4, or 6 mg/m2 was administered to pts with advanced malignancy & PS ≤2, LFTs ≤2.5 × normal, adequate hematopoietic & renal function, & normal resting MUGA. PK samples were analyzed by LC-MS. Data for pts in the fed state were compared to data obtained in previous cohorts of pts treated in the fasting state. Protein acetylation assessed by a novel flow cytometric assay & HDAC enzymatic activity were measured in peripheral blood mononuclear cells (PBMC). Results: 16 pts received a median of 2 cycles (1–5) of MS-275 2–6 mg/m2 with food. No DLT occurred on 2 or 6 mg/m2 (n = 3 each), while 1 pt on 4 mg/m2 (n = 10) had a DLT: grade 3 hypophosphatemia. For 2–6 mg/m2 other grade 3 toxicities were neutropenia & lymphopenia. Grade 1–2 toxicities in >1 pt were leucopenia, anemia, thrombocytopenia, fatigue, nausea, vomiting, headache, hypoalbuminemia, hypophosphatemia, hyponatremia, & hypocalcemia. MTD has not been reached; current dose level is 8 mg/m2. Comparing PK for fasting & fed pts on 2–4 mg/m2, there was no difference in Tmax (0.5h); average Cmax & AUC were 35% & 25% lower, respectively, in fed pts; this difference is not statistically significant. Interindividual variability in exposure to MS-275 increased from 52% in fasting pts to 100% in fed pts. PBMC protein acetylation & HDAC inhibition were seen at all dose levels (2–6 mg/m2) in fed pts. Of 9 pts evaluable for response (2–4 mg/m2), 2 of 6 pts on 4 mg/m2 had stable disease. Conclusions: MTD has not yet been established for MS-275 given with food on this schedule but is ≥4 mg/m2 weekly x4 q6 weeks. Interindividual variability in exposure increases with food. Whether intestinal absorption is decreased when MS-275 is given with food requires further evaluation with additional patients. Drug-related protein hyperacetylation & HDAC inhibition were observed. [Table: see text]

A phase 1 study of daily oral perifosine (P) with every 3-week paclitaxel (T)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13134-13134 ◽  
Author(s):  
T. F. Goggins ◽  
J. J. Nemunaitis ◽  
R. Shiffman ◽  
R. Birch ◽  
D. H. Berdeaux ◽  
...  
Keyword(s):  
Dose Level ◽  
Phase 1 ◽  
Performance Status ◽  
Single Agent ◽  
State Level ◽  
Hematologic Toxicity ◽  
Ecog Performance Status ◽  
Full Dose ◽  
Phase Ii Studies ◽  
Grade 3

13134 Background: Perifosine is a novel alkylphospholipid that has been shown to affect multiple signal transduction pathways including Akt, MAPK and JNK (Kondapaka, Mol. Canc. Ther 2: 1093–1103. 2003). Treatment with a taxane initially activates Akt, and persistent activation increases resistance to the drug (Vanderweele, Mol. Canc. Ther. 3: 1605–13, 2004). Methods: Twelve patients (pts) were enrolled on this study. T was given at a dose of 175 mg/m2 on day 8 (after 7 days of perifosine) of a 21 day cycle; this was to obtain a steady state level of P at the tumor before exposure to T. The intent of the protocol was to determine if full dose P could be delivered with 50 mg of perifosine given orally 1, 2 or 3 times a day on days 1–14 of each cycle. Results: Disease sites included lung 3, thyroid 3, breast 1, esophagus 1 and other 4, Median age was 66 (range 45 - 83); 6 pts were male and median ECOG performance status was 1 (range 0–2). All pts had received prior chemotherapy (median 2 regimens); 3 had prior treatment with a taxane. Three pts were entered at each dose level and the cohort expanded to 6 pts if 2 or more pts experienced a grade 3/4 non-hematologic toxicity (DLT) during cycle 1. A dose level was toxic if 4 or more pts experienced a DLT during cycle 1. A total of 30 cycles and a median of 2 cycles (range 1–11) per patient were delivered. There were no grade 3/4 hematologic toxicities. Full dose T was given in all treatment cycles. P dose reductions were required in 6% of cycles (50 mg - 7%, 100 mg - 0%, 150 mg - 7%). One patient missed one dose due to nausea and one pt was stopped due to diarrhea. The grade 3 toxicities for each cohort are given in the table below. The elevated glucose value was 321. Nine pts were evaluable for response; two pts with thyroid cancer had stable disease by the RECIST criteria for 9 and 10+ months. Conclusions: In this study the usual single agent doses of P (150 mg daily) & T (175 mg/m2 q 3 weeks) were given together without increasing the toxicities that would be expected from using each drug alone. Phase II studies are warranted to define activity of the combination. [Table: see text] [Table: see text]

A phase I study of bortezomib (PS-341) in pediatric patients with relapsed or refractory leukemia: A Children’s Oncology Group study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 9021-9021 ◽  
Author(s):  
T. M. Horton ◽  
P. A. Thompson ◽  
L. R. Bomgaars ◽  
P. C. Adamson ◽  
M. Krailo ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Single Agent ◽  
Altered Mental Status ◽  
26S Proteasome ◽  
Leukemic Cells ◽  
Peripheral Blood Mononuclear ◽  
Pediatric Leukemia ◽  
Leukemia Treatment

9021 Background: Bortezomib is a 26S proteasome inhibitor that is effective as a single agent for the treatment of multiple myeloma in adults. Bortezomib at a dose of 1.2 mg/m2 is well tolerated as a single agent in pediatric patients with solid tumors. This phase 1 study examined the tolerability and efficacy of bortezomib in pediatric patients with relapsed/refractory leukemia. Methods: Cohorts of 3–6 patients received bortezomib administered twice weekly (days 1, 4, 8 and 11) for two weeks every 21 days. Pharmacokinetics and NF-κB activation status were examined in peripheral blood mononuclear cells (PBMC) at 6, 12, and 24 hours following the first dose of bortezomib, and from bone marrow leukemic cells before treatment and on days 8 and 18 of the first treatment cycle. Results: Twelve patients (4 female, 8 male) (ALL=9, AML=3), median age 11y (range 1–18y), were enrolled at the 1.3 mg/m2 (6 enrolled, 3 evaluable) or 1.7 mg/m2 (6 enrolled, 2 evaluable) dose levels. Patients not fully evaluable for toxicity experienced disease progression prior to completing the first 21-day cycle of therapy. Two DLTs occurred at the 1.7 mg/m2 dose level. One patient had altered mental status and the other patient had febrile neutropenia associated with Grade 3 hypotension, Grade 4 renal insufficiency and hypoxia, followed by death on day 9 of cycle 1. No CRs or PRs were observed in the 10 patients evaluable for response. One patient had SD for 2 cycles. PK analysis (n= 5) revealed a Cl of 0.62 L/min/m2, Vd of 13 L/m2, and a terminal T1/2 of 12.6 h. NF-κB activation was inhibited in the leukemic blasts of 2 patients examined to date. Conclusions: Bortezomib was tolerated at 1.3 mg/m2 in children with relapsed/refractory leukemia. Although bortezomib appeared to inhibit NF-κB activation, it was ineffective as a single agent for pediatric leukemia treatment. No significant financial relationships to disclose.

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