A Phase I Trial of the Epigenetic Modulators Vorinostat, in Combination with Azacitidine (azaC) in Patients with the Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML): A Study of the New York Cancer Consortium

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3656-3656 ◽  
Author(s):  
Lewis R. Silverman ◽  
Amit Verma ◽  
Rosalie Odchimar-Reissig ◽  
Amanda LeBlanc ◽  
Vesna Najfeld ◽  
...  
Keyword(s):  
New York ◽  
Phase I ◽  
Optimization Design ◽  
Single Agent ◽  
Initial Response ◽  
Full Data ◽  
Hypomethylating Agent ◽  
Risk Patients ◽  
Grade 3

Abstract Background: The hypomethylating agent azacitidine (azaC) which can reverse epigenetic silencing, is the first agent demonstrated to alter the natural history of MDS and improve survival in higher-risk patients (Silverman JCO 2002, Fenaux Blood 2007). AzaC also produces comparable rates of response in patients with non-proliferative AML and appears to affect survival (Silverman JCO 2006). Time to response is slow with single agent azaC, requiring a median of 3 to 4 cycles to initial response and the CR + PR rates ranges from 7 to 27%. Vorinostat, a histone deacetylase inhibitor (HDACI) which inhibits class I and II HDAC, has demonstrated single agent activity in patients with MDS and AML with responses of 25% (Garcia-Manero Blood 2006). In vitro the 2 agents are synergistic in reactivating epigenetically silenced genes. The effect is sequence dependent requiring exposure to the hypomethylating agent first followed by the HDACI. This study was designed to test the safety of the combination and to determine the response rate and effects on the MDS/AML clone. Methods: In the phase I component eligible patients were entered into one of eight cohorts with the combination of vorinostat and azaC in a 3+3 dose escalating de-escalating design (see table). Results: As of the data cut for this submission 21 patients are evaluable for toxicity and response. Accrual to all 8 cohorts has been completed, full data will be available for the meeting. Among the 28 patients entered: 20 have MDS and 8 AML with median age 68. Responses among evaluable patients have occurred in 18 of 21 (86%); 9 CR, 2 CRi, (CR+CRi=53%) 7 HI, 2 SD. Median time to response is 2 cycles. Among patients with high risk MDS and AML 10/12 (83%) responded (5CR, 1CRi, 4 HI). Responses including CR occurred, but in 57% of patients the abnormal MDS/AML clone persisted, suggesting a modulating effect of the combination on the clone. A total of 171 cycles have been administered, range 1 to 17 with a mean 5 cycles. Eight patients have come off study for progression (1); relapse (2); co-morbidities (2); or consent withdrawal (3). No grade 3 or 4 non-hematologic toxicities in cycle 1 were observed. Grade 2 fatigue occurred during cycle 1 in 89% of patients in cohorts 2, 3 and 4. Grade 2 anorexia and fatigue occurred in cycle 1 in 31.6% and 57.9% of patients, respectively. The fatigue correlates with the scheduled duration of vorinostat administration with 14 days vorinostat (cohorts 1–4) associated with grade 2 and 7 days (cohorts 5–7) producing grade 1. Some suggestion of cumlative fatigue (grade 3) occurred in cycles 2 and beyond in cohorts 1, 3 and 4 with 14 days of vorinostat. However it did not result in discontinuation of therapy. Correlative biologic studies are underway. Conclusion: The combination of azaC and vorinostat can be safely combined, is well tolerated in repetitive cycles and is active in both lower and higher risk/AML patients with an OR and CR rate superior to azaC alone. AzaC at a dose of 55 mg/m2 appears to be optimal for combination. The phase II study will utilize an optimization design to further identify the optimal biologic/epigenetic effects among the three vorinostat schedules of 3, 7 or 14 days when combined. Cohort No of Pts AzaC dose mg/m2/d 1–7SQ Vorinostat dose Mg/d Total dose AzaC/Vorinostat Adverse Events anorexia/fatigue Response 2 patients withdrew consent before treatmen and were replaced in cohorts. 1 3 55 200 bid × 14d 385/5600 1;0;0/2;1;2 CR;CRi;CR 2 3 55 200 tid × 14d 385/8400 2;2;2/2;2;2 CR;HI;CR 3 3 75 200 tid × 14d 525/8400 1;0;1/2;0;2 NR;CR;CRi 4 3 75 200 bid × 14d 525/5600 2;1;2/2;2;2 IE;CR;HI 5 4 75 300 bid × 7d 525/4200 1;2;1/2;1;1 IE;SD;HI;SD 6 3 55 300 bid × 7d 385/4200 0;0;0/0;0;0 CR;HI;CR 7 5 55 200 bid ×7d 385/2800 0;2;2/0;1;1 IE;IE;CR;HI;HI 8 4 55 300 bid × 3d 385/1800 NA IE;HI;TE;TE

A Phase II Trial Of Epigenetic Modulators Vorinostat In Combination With Azacitidine (azaC) In Patients With The Myelodysplastic Syndrome (MDS): Initial Results Of Study 6898 Of The New York Cancer Consortium

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 386-386 ◽  
Author(s):  
Lewis R. Silverman ◽  
Amit Verma ◽  
Rosalie Odchimar-Reissig ◽  
Eric J. Feldman ◽  
Shyamala C. Navada ◽  
...  
Keyword(s):  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Phase I ◽  
Phase Ii ◽  
Single Agent ◽  
Response Duration ◽  
Initial Response ◽  
Cell Transplant ◽  
Grade 3

Abstract Background The hypomethylating agent (HMA) azaC reverses epigenetic silencing and is the first agent demonstrated to improve survival in patients with higher-risk MDS (Silverman et al JCO 2002, Fenaux et al Lancet Oncology 2009). Time to initial response with single agent azaC, is 3 to 4 cycles, the CR rate ranges from 7 to 17% and overall response is 45-50%. Vorinostat, a histone deacetylase inhibitor (HDACI) which inhibits class I and II HDAC, has demonstrated single agent activity in patients with MDS with responses of 20% (Garcia-Manero Blood 2006). In vitro the 2 agents are synergistic in reactivating epigenetically silenced genes. The effect is sequence-dependent requiring exposure to the HMA first followed by the HDAC. We conducted a phase I pilot study of escalating and de-escalating doses of the 2 drugs in combination in 8 cohorts and demonstrated broad activity with responses ranging up to 80% across all of the cohorts tested (Blood 2008). Purpose To determine the response rate of patients treated with the combination of vorinostat and azacitidine at the doses established as safe and effective in Phase I in an expanded cohort of patients with MDS. Methods In the phase II component 3 schedules of the combination were chosen based on response and adverse event profile for further evaluation. Eligible patients were entered into one of 3 cohorts with the combination (see table 1): cohort 1: azaC 55 mg/m2/d 1-7 SC, vorinostat 200mg po Bid d3-16; cohort 2: azaC 75 mg/m2/d 1-7 SC, vorinostat 300mg po Bid d3-9; cohort 3: azaC 55 mg/m2/d 1-7 SC, vorinostat 300mg po Bid d3- 9. Patients with IPSS int-1, -2 and high-risk disease were eligible. Patients with secondary MDS were eligible, those with AML were excluded. Using a simon 2 stage design 13 patients were entered in each cohort and assessed for response, scored according to IWG 2006 criteria and toxicity. Results 40 patients have been entered and 39 (21 male, 18 female) are evaluable for toxicity and 33 for response, 1 pt was registered but never treated. IPSS classification among the 39 patients: int-1 8; int-2 12; high-risk 12; unclassified 7, with median age 67 (23-79). Responses among evaluable patients have occurred in 23 of 33 (70%); 10 CR, 4 CRi, (CR+CRi=42%) 9 HI, 5 SD, 5 NR. Median time to response is 2 cycles (8 weeks). Responses by cohort (table 1) are 70%, 73% and 67% for cohort 1, 2 and 3, respectively. Analysis for the MDS clone at the time of best response demonstrated the persistence of the clone in 45% of patients as marked by cytogenetic or FISH abnormalities, suggesting a modulating rather than cytotoxic effect of the combination on the clone. Cycles administered, range from 1 to 26+ with a median of 6 cycles. Median duration of response is 16 months overall and 9.5, 23 and 27 months, respectively for cohorts 1, 2 and 3. Eighteen patients have come off study for: death or due to disease complications (6); co-morbidities (2); consent withdrawal (5); and withdrawal for stem cell transplant (3). Median OS is 21.1 months and is 10.1, 37.4 and 19 months for cohorts 1, 2, and 3 respectively (NS). Grade 3 fatigue occurred during cycle 1, 2 or 3 in cohort 1 (8%), cohort 2 (16%) and cohort 3 (8%). GI toxicity grade 3 (vomiting, diarrhea, dehydration) occurred in 8% of patients in each of the cohorts. There was no suggestion of cumulative toxicity for either fatigue or GI adverse events. Correlative biologic study analysis is underway. Conclusion The combination of azaC and vorinostat can be safely administered, and is well tolerated in repetitive cycles. The dose of azaC in cohort 2 adheres to the FDA approved dose and schedule. OR and CR rates and time to initial response are comparable among the cohorts and these data suggest that the combination is superior to published results of azaC alone. Cohorts 2 and 3, with vorinostat administered for 7 days, appears to be associated with longer response duration and OS. An intergroup study (SWOG-S1117) comparing azaC and vorinostat to either azaC alone or combined with lenalidomide is underway utilizing the doses and schedule in cohort 2 from this study. Correlative studies that may shed light on mechanism of action or guide patient selection are being conducted. Supported in part by NYCC- N01 CM-62204 and the Henry and Mickey Taub Foundation. Disclosures: Silverman: Merck: Research Funding. Off Label Use: vorinostat for treatment of patients with a myelodysplastic syndrome investigational use.

Phase I Trial of Everolimus and Rituximab or Everolimus, Bortezomib and Rituximab in Relapsed or Relapsed/Refractory Waldenstrom's Macroglobulinemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2705-2705 ◽  
Author(s):  
Irene M. Ghobrial ◽  
Erica N Boswell ◽  
Ranjit Banwait ◽  
Tiffany Poon ◽  
Amanda Donovan ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Recommended Dose ◽  
Synergistic Activity ◽  
Advisory Committees ◽  
Overall Response ◽  
Risk Patients ◽  
Grade 3

Abstract Abstract 2705 INTRODUCTION: This study aimed to determine the safety and maximum tolerated dose of the combination of everolimus and rituximab, or everolimus, bortezomib, and rituximab in relapsed and/or relapsed/refractory Waldenstrom Macroglobulinemia. This trial was based on our preclinical studies that demonstrated synergistic activity of everolimus and bortezomib with rituximab in WM cell lines, and based on our favorable clinical experience with everolimus as single agent in the treatment of WM. METHODS: Eligibility criteria include: 1) patients with relapsed or relapsed/refractory WM with any number of prior lines of therapy, including everolimus and bortezomib 2) not completely refractory to rituximab 3) measurable disease by monoclonal IgM protein in the serum and lymphoplasmacytic cells in the bone marrow, 4) Not receiving chemotherapy > 3 weeks, or biological/novel therapy for WM > 2 weeks. A cycle is 28 days and a total of 6 cycles are given, followed by everolimus maintenance for 2 years. Two stages with a total of four dose levels were planned. In stage A, patients received everolimus at the recommended dose orally daily for 28 days and rituximab at the recommended dose IV on days 1, 8, 15, and 22 every 28 days at cycle 1 and 4 only. In stage B, patients received everolimus at the recommended dose orally daily for 28 days, bortezomib at the recommended dose IV on days 1, 8, 15 every 28 days, and rituximab at the recommended dose IV on days 1, 8, 15, and 22 every 28 days at cycle 1 and 4 only. Patients were assessed for response after every cycle. Subjects who had a response continued on therapy for a total of 6 cycles, and then continued on to maintenance therapy with everolimus alone until progression (or for a maximum of 24 months). Because of the potential of an IgM flare after rituximab, patients who showed an increase in IgM after rituximab in the first 3 months were not deemed as having progressive disease unless they showed evidence of clinical progression. To examine the in vivo effect of everolimus, bortezomib, and rituximab, peripheral blood samples were obtained from patients on days 1, 8, 15, and 22 at cycle 1; and on day 1 only at all subsequent cycles. RESULTS: Twenty-three patients were enrolled in this phase I clinical trial from April 2009 to July 2011. The median age is 61 (range, 52–73) yrs and the median lines of prior therapy is 2 (range, 1–8) with all patients receiving prior rituximab and 12 (52%) receiving prior bortezomib. The median number of cycles on therapy was 3.5 (range, 0–15). Overall, this combination therapy is very well tolerated. Grade 4 toxicities included: neutropenia (8.7%), leukopenia (4.3%), thrombocytopenia (17.4%), lymphopenia (4.3%) and hypertriglyceridemia (4.3%). Grade 3 toxicities included: neutropenia (21.7%), leukopenia (26.1%), anemia (13%), lymphopenia (17.4%), pneumonitis (4.3%), SGPT (4.3%), neuropathy (4.3%), Herpes zoster reactivation (4.3%), hyperglycemia (4.3%) and hypernatremia (4.3%). 1 patient discontinued therapy due to grade 3 anemia. Nineteen patients are currently evaluable for response, including 1 (5%) very good partial response (VGPR) and 9 (47%) minimal response (MR), for an overall response rate including MR of 10/19 (53%) in this relapsed/refractory population. Furthermore, overall response including MR in stage A (everolimus/rituximab) was 2/6 (33%) and 8/13 (62%) in stage B (everolimus/bortezomib/rituximab). Additionally, 9 (39%) patients achieved stable disease, and 4 (17%) are early on therapy and not been yet assessed. CONCLUSIONS: The combination of everolimus, bortezomib, and rituximab is generally well tolerated, and importantly no grade 3/4 neuropathy was seen. Moreover, no dose limiting toxicities were observed even at the maximum dose evaluated. The responses observed to date in this relapsed/refractory population are encouraging. Based on the safety of this phase I study, the phase II study of two arms, everolimus/rituximab for low risk patients and everolimus/bortezomib/rituximab for intermediate and high risk patients is underway. Disclosures: Ghobrial: Bristol-Myers Squibb: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Noxxon: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Bortezomib and everolimus in WM. Anderson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Acetylon: Membership on an entity's Board of Directors or advisory committees. Richardson:Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Treon:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

A Phase I Study of the Combination of Decitabine with Lenalidomide for Patients with High Risk (IPSS Int-2 or High) Myelodysplastic Syndrome

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5029-5029
Author(s):  
Carlos Manuel de Castro ◽  
Donna Adams ◽  
Arati V Rao ◽  
Joseph O. Moore ◽  
Jon P. Gockerman ◽  
...  
Keyword(s):  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Phase I ◽  
Common Good ◽  
Phase I Study ◽  
Single Agent ◽  
Prior Treatment ◽  
Hypomethylating Agent ◽  
Secondary Objective ◽  
Grade 3

Abstract Abstract 5029 Background: Decitabine and lenalidomide have demonstrated single agent activity in patients with myelodysplastic syndromes (MDS). The addition of lenalidomide to decitabine in patients with high risk MDS may improve responses through distinct mechanisms. A phase I study of azacytidine and lenalidomide has previously demonstrated the feasibility of the combination of a hypomethylating agent with lenalidomide and did suggest higher response rates. (Sekeres M, et al. JCO 2010) Methods: We conducted a 3×3 cohort design. Patients with high risk MDS who had received prior hypomethylating agent were eligible for the study. Patients were treated with decitabine 20mg/m2 IV over 1 hour daily on days 1–5. Lenalidomide was escalated in each cohort using a dose of 5 mg po daily for 21 days in cohort 1 and 10 mg po daily for 21 days in cohort 2. Additional cohorts using 15 mg and 25 mg of lenalidomide are planned but have not yet been entered. Cycles were repeated every 28 days if count recovery was adequate. Toxicity was assessed by NCI CTCAE v3.0 criteria. Responses (a secondary objective) were assessed using IWSG criteria. Results: Seven patients have been entered into this study and are evaluable for toxicity and response. Median age is 74 years (69–77). Because of 1 death in cohort 1 (felt to be due to respiratory failure in a patient with severe COPD and not related to study drugs), the cohort was expanded to 6 patients. No other deaths occurred on study. One patient has been entered on cohort 2. No grade 3 or 4 toxicities were seen in the other 6 patients. Myelosuppression is common but does not appear to be worse than decitabine alone. In the 6 patients in which response could be assessed, there were 2 complete responses (CRs) and 3 partial responses (PRs). One patient progressed to AML after one cycle. Responses were seen in the 3 patients that had received prior treatment with hypomethylating agents (1 CR, 2 PR). Duration of responses ranged from 4 months to 16 months. Conclusion: The combination of decitabine and lenalidomide has been well tolerated in patients with high-risk MDS. The maximum tolerate dose has not been reached, although myelosupression is common. Good responses have been seen even in patients with prior treatment with a hypomethylating agent. Disclosures: Off Label Use: Decitabine in combination with lenalidomide for high risk myelodysplastic syndrome. Rizzieri:Celgene: Speakers Bureau.

Phase I Study of AR-42 in Relapsed Multiple Myeloma and Lymphoma.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2955-2955 ◽  
Author(s):  
Craig C. Hofmeister ◽  
Zhongfa Liu ◽  
Mindy A Bowers ◽  
Pierluigi Porcu ◽  
Joseph M. Flynn ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cell ◽  
Phase I ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Class I ◽  
Qtc Prolongation ◽  
Grade 3

Abstract Abstract 2955 Introduction: Deacetylase (DAC) inhibitors show promise as anti-neoplastic agents, the approved drugs are weak inhibitors of class I and II DACs or potent inhibitors of class I DAC only, and have suboptimal activity or unacceptable toxicities. AR-42 is a class I/II DAC-I designed at OSU that demonstrates a 20,000-fold improvement in DAC inhibitory potency relative to the parent molecule (IC50=16 nM) with greater antiproliferative effects than Vorinostat in vitro and in vivo (Kulp et al, Clin Cancer Res, 2006 and Lucas et al, PLoS One, 2010). Methods: OSU 09102 (NCI 9119) is a first-in-man single agent, cohorts-of-3 phase I dose escalation study in adult patients with relapsed CLL, lymphoma (NHL), or multiple myeloma (MM) with normal kidney and liver function. Patients received AR-42 orally M-W-F in cycles of 28 days (3 weeks of 3-times-per-week dosing followed by a 7-day break). Moderate cell count suppression was allowed with an absolute neutrophil cutoff of 1000/μL, platelets 3 50,000/μL and hemoglobin 3 10 g/dL. In the first stage of dose escalation, each dose level increased by 100% until the first grade 2, drug-related toxicity was observed. Subsequent dose increases will be approximately 33% increase with accrual in cohorts of 3 patients. For pharmacokinetic analysis, plasma was obtained at 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 4, 8, 10, 24, and 48 hours after dosing on day 1 and day 19 (only up to 24 h), and then kept at –80°C until analysis. Results: We enrolled 3 patients at 20 mg (MM, MM, NHL), 3 patients at 40 mg (MM) with a transition to a slower dose escalation due to a grade 2 thrombocytopenia. Three more patients were enrolled at 40 mg (MM, MM, T-cell NHL), then 7 patients at 50 mg (MM × 4, follicular × 1, T-cell NHL × 2). One myeloma patient was enrolled at 70 mg. In the 40 mg cohort, related toxicities include 2 grade 3 and 2 grade 2 thrombocytopenia, 1 grade 3 neutropenia, 1 grade 2 vomiting, and 2 grade 1 QTc prolongation. In the 50 mg cohort 1 grade 4 and 3 grade 3 thrombocytopenia, 2 grade 3 neutropenia, 4 grade 2 fatigue, 2 grade 2 muscle spasm, 1 grade 2 blurred vision/dizziness, 3 grade 1 QTc prolongation, and 3 grade 1 nausea. Accrual was temporarily halted for a safety analysis Mar-2012 focused on the 50 mg cohort toxicities – one grade 4 thrombocytopenia considered a DLT, one patient found dead on cycle 2 day 10 without prior evidence of QTc prolongation, and one patient with reproducible dizziness and blurry vision. AR-42 was detected 15 mins after dose in 12 of 17 patients, suggesting rapid absorption. The time to reach the peak concentration in plasma (Tmax) varied from 1.5 hours to 4 hours. The Cmax (see chart) and AUC of AR-42 was not increased proportionally with doses, suggesting that the PK of AR-42 is not linear in the 20–50 mg range. Conclusion: The Cmax achieved at the 40 mg and 50 mg dose levels is adequate for HDAC inhibition in vitro and minor clinical responses were observed in myeloma and T-cell lymphoma as a single agent in the 40 mg cohort (see monoclonal proteins chart), hence 40 mg TIW 3-weeks-on and 1-week-off was declared the MTD. Complete pharmacokinetic, toxicity, and results from brief fatigue inventory will be presented at the meeting. AR-42 does not have the severe fatigue and gastrointestinal side effects of other broad DAC inhibitors and may be suitable for combination phase Ib trials in T-cell lymphoma and myeloma. Disclosures: No relevant conflicts of interest to declare.

A phase II study of single agent depsipeptide (DEP) in patients (pts) with radioactive iodine (RAI)-refractory, metastatic, thyroid carcinoma: Preliminary toxicity and efficacy experience

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5554-5554 ◽  
Author(s):  
Y. B. Su ◽  
R. M. Tuttle ◽  
M. Fury ◽  
R. Ghossein ◽  
B. Singh ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Phase I ◽  
Single Agent ◽  
Whole Body ◽  
Secondary Outcome ◽  
Cardiac Events ◽  
Grade 5 ◽  
Metastatic Setting ◽  
Grade 3

5554 Background: RAI-refractory thyroid cancer carries a poor prognosis, and no effective systemic therapy exists. DEP is a potent histone deacetylase inhibitor with broad in vitro and phase I anti-tumor activity, and has restored sodium-iodide symporter expression and RAI avidity in thyroid cancer cell lines. Methods: Eligible pts have confirmed papillary, follicular, or Hürthle cell carcinoma, progressive measurable disease, and adequate hepatic/renal function. All pts are RAI-refractory by diagnostic RAI whole body scan (WBS). Prior chemotherapy in the recurrent/metastatic setting, and history of significant cardiac disease are exclusions. DEP 13 mg/m2 IV is given on day 1, 8, and 15, every 28 days. A novel Simon 2-stage design specifies an initial accrual of 21 pts, with expansion to 41 total pts if 2 RECIST responses or 6 pts with PFS at 6 months are observed. Primary outcome is RECIST response rate. Change in RAI avidity (by diagnostic RAI WBS) is a secondary outcome. Results: To date, 14 pts have been enrolled: female 50%, median age 62 (42–78), median Karnofsky 90 (70–100), papillary/follicular/Hürthle histology (7/1/6). Grade 3–5 toxicities possibly related to drug: grade 5 sudden death (1); no grade 4 toxicity; grade 3 toxicity - fatigue (1), dysphagia (1), dyspnea (1). No grade 3 thrombocytopenia (phase I DLT) has been observed. Grade 1 (6) and grade 2 (4) fatigue have been common. As a result of the grade 5 event, protocol accrual and treatment were suspended temporarily. After NCI-CTEP review, more restrictive cardiac exclusions were added and protocol accrual was resumed. Response at 2 months: stable disease (4); progression (2); inevaluable (6, due to protocol suspension); withdrew consent (1); too early (1). In a proof-of-principle event, clinically significant restoration of RAI avidity was observed in a 78 year-old woman with papillary carcinoma. Per protocol, she was taken off study and given treatment-dose RAI; post-therapy WBS confirmed dramatic RAI avidity. Conclusions: Preliminary signs of in vivo reversal of RAI resistance have been observed. Accrual continues with more restrictive cardiac exclusions, and close surveillance for cardiac events. No significant financial relationships to disclose.

scholarly journals EPCT-19. A PHASE I STUDY OF RIBOCICLIB AND EVEROLIMUS FOLLOWING RADIATION THERAPY IN CHILDREN WITH NEWLY DIAGNOSED NON-BIOPSIED DIFFUSE PONTINE GLIOMAS (DIPG) AND RB+ BIOPSIED DIPG AND HIGH GRADE GLIOMAS (HGG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii307-iii307
Author(s):  
Mariko DeWire ◽  
James Leach ◽  
Christine Fuller ◽  
Peter de Blank ◽  
Trent Hummel ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Studies ◽  
High Grade ◽  
Newly Diagnosed ◽  
High Grade Gliomas ◽  
Grade 3 ◽  
Expansion Cohort

Abstract Genomic aberrations in the cell cycle and mTOR pathways have been reported in diffuse pontine gliomas (DIPG) and high-grade gliomas (HGG). Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dose (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus administered during maintenance therapy following radiotherapy was determined in the phase I study as a rolling 6 design. Ribociclib and everolimus were administered once daily for 21 days and 28 days, respectively starting two-four weeks post completion of radiotherapy. All HGG patients and any DIPG patient who had undergone biopsy were screened for RB protein by immunohistochemistry. Eighteen eligible patients enrolled (median age 8 years; range: 2–18). Six patients enrolled at dose levels 1,2, and 3 without dose limiting toxicities (DLT). Currently, five patients are enrolled at dose level 3 expansion cohort. The median number of cycles are 4.5 (range: 1–20+). Among the expansion cohort, one dose limiting toxicity included a grade 3 infection and one patient required a dose reduction in course 3 due to grade 3 ALT and grade 4 hypokalemia. The most common grade 3/4 adverse events included neutropenia. Preliminary pharmacokinetic studies on 12 patients suggest an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus following radiotherapy in newly diagnosed DIPG and HGG is anticipated to be 170 mg/m2/day x 21 days and 1.5 mg/ m2/day every 28 days which is equivalent to the adult RP2D.

scholarly journals EPCT-17. A PHASE I AND SURGICAL STUDY OF RIBOCICLIB AND EVEROLIMUS IN CHILDREN WITH RECURRENT OR REFRACTORY MALIGNANT BRAIN TUMORS: PEDIATRIC BRAIN TUMOR CONSORTIUM INTERIM REPORT

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii307-iii307
Author(s):  
Mariko DeWire ◽  
Christine Fuller ◽  
Olivia Campagne ◽  
Tong Lin ◽  
Haitao Pan ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Single Agent ◽  
Pediatric Brain Tumor ◽  
Pi3k Pathway ◽  
Neurosurgical Procedures ◽  
Common Grade ◽  
Grade 3

Abstract Genomic aberrations in the cell cycle and PI3K pathway are commonly observed in recurrent childhood brain tumors. Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dosage (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus was determined in the Phase I study and ribociclib concentrations were characterized in plasma and tumor in children undergoing neurosurgical procedures. Following resection, eligible patients were enrolled in the Phase I study according to a rolling 6 design and received ribociclib and everolimus once daily for 21 days and 28 days, respectively. Patients undergoing surgery received ribociclib at the pediatric RP2D (350 mg/m2/day) for 7–10 days pre-operatively. Pharmacokinetic samples were collected on both cohorts and analyzed in nine patients on phase I study. Sixteen eligible patients enrolled on phase I study (median age 10.3 years; range: 3.9–20.4) and 5 patients were enrolled on the surgical cohort (median age 11.4 years; range: 7.2–17.1). Six patients enrolled at dose level 1 without dose limiting toxicities (DLT). Two of the three patients at dose level 2 experienced DLT (grade 3 hypertension and grade 4 ALT). The most common grade 3/4 toxicities were lymphopenia, neutropenia, and leucopenia. Everolimus concentrations following administration of everolimus alone were lower than those following drug combination, suggesting an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus in recurrent CNS tumors is 120 mg/m2 and 1.2 mg/ m2 daily for 21 days and 28 days, respectively.

scholarly journals ACTR-59. A PHASE 1 STUDY OF BPM31510 PLUS VITAMIN K IN SUBJECTS WITH HIGH-GRADE GLIOMA THAT HAS RECURRED ON A BEVACIZUMAB-CONTAINING REGIMEN

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi27-vi27
Author(s):  
Lawrence Recht ◽  
Reena Thomas ◽  
Sophie Bertrand ◽  
Priya Yerballa ◽  
Gordon Li ◽  
...  
Keyword(s):  
Phase I ◽  
Vitamin K ◽  
Phase I Study ◽  
Phase 1 ◽  
High Grade Glioma ◽  
High Grade ◽  
Open Label ◽  
Open Label Phase ◽  
Grade 3

Abstract BACKGROUND High-grade gliomas (HGG) are characterized by dysregulated metabolism, utilizing glycolysis for energy production to support unrestricted growth. BPM 31510, an ubidecarenone (coenzyme Q10) containing lipid nanodispersion, causes a switch in cancer energy sourcing from glycolysis towards mitochondrial oxidative phosphorylation in vitro, reversing the Warburg effect and suggesting potential as an anti-tumor agent. The current study is a phase I study of BPM31510 + vitamin K in GB with tumor growth after bevacizumab (BEV). METHODS This is an open-label phase I study of BPM31510 continuous infusion with weekly vitamin K (10mg IM) in HGG patients using an mTPI design, starting at 110mg/kg, allowing for a single dose de-escalation and 2 dose-escalations. Patients had received first-line ChemoRadiation and were in recurrence following a BEV containing regimen. RESULTS 9 eligible and evaluable patients completed the 28 day DLT period. 8 patients had primary GB, 1 had anaplastic astrocytoma with confirmed pathologic transformation to GB. Median age was 55 years (27–67) and median KPS 70 (60–90) at enrollment. 4 patients were treated at the highest dose 171mg/kg, where there was a single DLT: Grade 3 AST & ALT. The most common grade 1–2 AEs possibly, probably or definitely related to drug were elevated AST, rash, and fatigue, each occurring in 3 patients. Median OS for 9 eligible/evaluable patients was 128 days (95% CI: 48–209) while PFS was 34 days (CI of mean 8.9). 3 patients are currently alive; 2 patients have survived >1 year. PK/PD data are being processed and will be presented. CONCLUSION This study confirms that BPM 31510 + vitamin K is safe and feasible in treatment-refractory HGG patients. Though this study demonstrates safety at 171mg/kg, the proposed dose for future studies in GB, based on additional pre-clinical and non-GB clinical data is 88mg/kg.

Sequences of topotecan and cisplatin: phase I, pharmacologic, and in vitro studies to examine sequence dependence.

1996 ◽  
Vol 14 (12) ◽  
pp. 3074-3084 ◽  
Author(s):  
E K Rowinsky ◽  
S H Kaufmann ◽  
S D Baker ◽  
L B Grochow ◽  
T L Chen ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Topoisomerase I ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
In Vitro Studies ◽  
Pharmacokinetic Studies ◽  
Sequence Dependence ◽  
Renal Tubular

PURPOSE A phase I and pharmacologic study was performed to evaluate the feasibility of administering the topoisomerase I (topo I) inhibitor topotecan (TPT) in combination with cisplatin (CDDP) in minimally pretreated adults with solid tumors. The study was designed to evaluate the magnitude of the toxicologic and pharmacologic differences between the two sequences of drug administration. MATERIALS AND METHODS TPT was administered as a 30-minute infusion daily for 5 days and CDDP was given either before TPT on day 1 or after TPT on day 5. Each patient was treated with both schedules on an alternating basis every 3 weeks. Sequential dose escalation of TPT or CDDP resulted in three dosage permutation of TPT/CDDP (mg/m2): 0.75/50, 1/50, and 0.75/75. After the maximum-tolerated dose (MTD) level was achieved, the feasibility of using granulocyte colony-stimulating factor (G-CSF) to permit further dose escalation was studied. To examine the interaction of TPT and CDDP in vitro, human A549 lung cancer cells were exposed to these agents concurrently and sequentially. RESULTS Dose-limiting neutropenia and thrombocytopenia resulted after the doses of TPT or CDDP were increased to greater than 0.75 and 50 mg/m2, respectively, without and with G-CSF. The sequence of CDDP before TPT induced significantly worse neutropenia and thrombocytopenia than the alternate sequence. In vitro studies failed to provide any evidence for the differences in the cytotoxicity of these two sequences. Instead, pharmacokinetic studies suggested that the differences in toxicity were due, in part, to lower TPT clearance and exposure when CDDP preceeds TPT, possibly due to subclinical renal tubular toxicity induced by CDDP. CONCLUSION The sequence of CDDP before TPT at doses of 50 and 0.75 mg/m2, respectively, is recommended for subsequent clinical trials in tumor types in which both agents have significant single-agent activity. The potential for sequence-dependent cytotoxic, toxicologic, and pharmacologic effects should be evaluated in concurrent clinical and laboratory studies in the course of developing combination chemotherapy regimens that consist of topo I-targeting agents and other antineoplastic agents, particularly DNA-damaging agents.

Phase I Assessment of the Pharmacokinetics, Metabolism, and Safety of Emitefur in Patients With Refractory Solid Tumors

2000 ◽  
Vol 18 (19) ◽  
pp. 3423-3434 ◽  
Author(s):  
J. Nemunaitis ◽  
R. Eager ◽  
T. Twaddell ◽  
A. Corey ◽  
K. Sekar ◽  
...  
Keyword(s):  
Steady State ◽  
Phase I ◽  
Solid Tumors ◽  
Prolonged Exposure ◽  
Circadian Variation ◽  
Pharmacokinetic Profile ◽  
Maximum Tolerated Dose ◽  
Minimum Effective Concentration ◽  
Grade 3

PURPOSE: To determine the toxicities, dose-limiting toxicities (DLT), maximum-tolerated dose, and pharmacokinetic profile of emitefur (BOF-A2) in patients with advanced solid tumors. METHODS: This was a phase I dose-escalating trial in which cohorts of patients received BOF-A2 (cohort 1, 300 mg/m2 orally [PO] tid; cohort 2, 200 mg/m2 PO tid; cohort 3, 200 mg/m2 bid; and cohort 4, 250 mg/m2 bid) for 14 consecutive days followed by 1 week of rest (cycle 1). Pharmacokinetics, toxicity, and tumor response were monitored. RESULTS: Nineteen patients received 110 cycles (three patients in cohort 1, three patients in cohort 2, 10 patients in cohort 3, and three patients in cohort 4). DLT (grade 3 stomatitis, diarrhea, leukopenia) was observed in cohorts 1, 2, and 4. Pharmacokinetics indicated that prolonged systemic expression of fluorouracil (5-FU) is maintained after administration of BOF-A2 at a dose of 200 mg bid for 14 days. The mean steady-state concentration of plasma 5-FU was ≥ 24 ng/mL, which was 184-fold greater than the minimum effective cytotoxic concentration in vitro. Lack of variation of 5-FU trough levels within a day at steady-state indicates suppression of circadian variation. One patient in cohort 3 achieved a partial response and five patients maintained stable disease in excess of 6 months. CONCLUSION: BOF-A2 at a dose of 200 mg PO bid for 14 days followed by 7 days of rest is well tolerated. Prolonged exposure to 5-FU above the predicted preclinical minimum effective concentration is maintained, without evidence of circadian variation. Furthermore, evidence of antitumor activity is suggested.

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