Phase I Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of PTK787/ZK 222584 Administered Twice Daily in Patients With Advanced Cancer

2005 ◽  
Vol 23 (18) ◽  
pp. 4162-4171 ◽  
Author(s):  
Anne L. Thomas ◽  
Bruno Morgan ◽  
Mark A. Horsfield ◽  
Anthony Higginson ◽  
Andrea Kay ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Phase I ◽  
Single Agent ◽  
Angiogenesis Inhibitor ◽  
Biologically Active ◽  
Pharmacokinetic Data ◽  
Vegf Receptor ◽  
Dce Mri ◽  
Grade 3

Purpose PTK787/ZK 222584 (PTK/ZK) is an oral angiogenesis inhibitor targeting all known vascular endothelial growth factor (VEGF) receptor tyrosine kinases, including VEGFR-1/Flt-1, VEGFR-2/KDR, VEGFR-3/Flt-4, the platelet-derived growth factor receptor tyrosine kinase, and the c-kit protein tyrosine kinase. In this phase I dose-escalating study, PTK/ZK was administered bid to exploit the theoretical advantage of maintaining constant drug levels above a threshold known from preclinical data to interfere with VEGF receptor signaling. Patients and Methods Forty-three patients with advanced cancers received single-agent PTK/ZK at doses of 150 to 1,000 mg orally bid. Assessments for safety and pharmacokinetics were performed. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used as a pharmacodynamic marker of response. Results At 1,000 mg bid, the dose-limiting toxicity of reversible grade 3 lightheadedness was observed. Dose-related grade 3 fatigue and vomiting were observed but these were not dose-limiting. Pharmacokinetic data confirmed that PTK/ZK exposure increased with increasing dose up to 500 mg bid and appeared to plateau at higher doses. A greater than 40% reduction in the DCE-MRI bidirectional transfer constant (Ki) at day 2 predicted for nonprogression of disease. Conclusion The maximum-tolerated oral dose of PTK/ZK is 750 mg orally bid. DCE-MRI and pharmacokinetic data indicate that PTK/ZK ≥ 1,000 mg total daily dose is the biologically active dose.

scholarly journals Phase I Pharmacokinetic and Pharmacodynamic Study of Pazopanib in Children With Soft Tissue Sarcoma and Other Refractory Solid Tumors: A Children's Oncology Group Phase I Consortium Report

2013 ◽  
Vol 31 (24) ◽  
pp. 3034-3043 ◽  
Author(s):  
Julia L. Glade Bender ◽  
Alice Lee ◽  
Joel M. Reid ◽  
Sylvain Baruchel ◽  
Timothy Roberts ◽  
...  
Keyword(s):  
Growth Factor ◽  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Phase I ◽  
Solid Tumors ◽  
Angiogenesis Inhibitor ◽  
Antiangiogenic Effect ◽  
Dce Mri ◽  
Potential Clinical Benefit ◽  
Pharmacodynamic Study

Purpose Pazopanib, an oral multikinase angiogenesis inhibitor, prolongs progression-free survival in adults with soft tissue sarcoma (STS). A phase I pharmacokinetic and pharmacodynamic study of two formulations of pazopanib was performed in children with STS or other refractory solid tumors. Patients and Methods Pazopanib (tablet formulation) was administered once daily in 28-day cycles at four dose levels (275 to 600 mg/m2) using the rolling-six design. Dose determination for a powder suspension was initiated at 50% of the maximum-tolerated dose (MTD) for the intact tablet. Ten patients with STS underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scanning at baseline and 15 ± 2 days after initiation of pazopanib at the tablet MTD. Results Fifty-three patients were enrolled; 51 were eligible (26 males; median age, 12.9 years; range, 3.8 to 23.9 years). Hematologic and nonhematologic toxicities were generally mild, with dose-limiting lipase, amylase, and ALT elevation, proteinuria, and hypertension. One patient with occult brain metastasis had grade 4 intracranial hemorrhage. The MTD was 450 mg/m2 for tablet and 160 mg/m2 for suspension. Steady-state trough concentrations were reached by day 15 and did not seem to be dose dependent. One patient each with hepatoblastoma or desmoplastic small round cell tumor achieved a partial response; eight patients had stable disease for ≥ six cycles, seven of whom had sarcoma. All patients with evaluable DCE-MRI (n = 8) experienced decreases in tumor blood volume and permeability (P < .01). Placental growth factor increased, whereas endoglin and soluble vascular endothelial growth factor receptor-2 decreased (P < .01; n = 41). Conclusion Pazopanib is well tolerated in children, with evidence of antiangiogenic effect and potential clinical benefit in pediatric sarcoma.

Phase I trial of PTK787/ZK222584 (PTK/ZK) in combination with carboplatin (C) and paclitaxel (T) in platinum-sensitive recurrent epithelial ovarian (EOC), fallopian tube (FT), or primary peritoneal (PPC) cancers

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5564-5564 ◽  
Author(s):  
M. M. Juretzka ◽  
C. Aghajanian ◽  
M. L. Hensley ◽  
W. P. Tew ◽  
D. Spriggs ◽  
...  
Keyword(s):  
Growth Factor ◽  
Phase I ◽  
Tyrosine Kinases ◽  
Angiogenesis Inhibitor ◽  
Growth Factor Receptor ◽  
Liver Function Tests ◽  
Maximum Tolerated Dose ◽  
Vegf Receptor ◽  
Open Label ◽  
Platinum Sensitive

5564 Background: Targeting vascular endothelial growth factor (VEGF) in patients (pts) with ovarian cancer achieves objective responses. PTK/ZK is an orally active angiogenesis inhibitor which blocks all known VEGF receptor and platelet-derived growth factor receptor tyrosine kinases. A previous study administered PTK/ZK only on days 3–21 of C and T cycle based on pre-clinical data suggesting PTK/ZK increases T levels (PROC ASCO # 5042, 2005), and recent data supports bid dosing (JCO 18:1–10, 2005). Methods: In this open label, single institution phase I study, pts with platinum sensitive recurrent EOC, FT, or PPC were treated with C and T every 21 days with increasing continuous daily doses of PTK/ZK (250 mg to 1,250mg with bid dosing). Primary endpoints were safety and maximum tolerated dose (MTD). Pharmacokinetic (PK) analysis is planned to describe C and T pharmacokinetics when combined with PTK/ZK. Results: To date, 14 pts with median age 61 (range 45–73) have been enrolled on the first 3 dose levels, including 13 EOC and 1 PPC. All patients were evaluable for toxicity and 8 were evaluable for investigator assessed response. MTD has not been reached. Febrile neutropenia was dose limiting toxicity requiring expansion at levels II and III. PK analysis is ongoing. To date, best responses are: 4 (PR), 3 (SD) and 1 (POD). Other G III toxicity included: C hypersensitivity reaction (1, gr 3), hyperglycemia (4, gr 3), hypertension (1, gr 3), diarrhea (1, gr 3), and elevated liver function tests (1, gr 3). Conclusion: PTK/ZK can be administered continuously in combination with standard doses of C and T using bid dosing. MTD is not yet reached and accrual is ongoing. PK data and MTD will be presented. Supported by Novartis and Bayer Schering Pharma. [Table: see text] No significant financial relationships to disclose.

Safety and pharmacokinetics of intravenous VEGF Trap plus FOLFOX4 in a combination phase I clinical trial of patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13061-13061 ◽  
Author(s):  
M. Mulay ◽  
S. A. Limentani ◽  
M. Carroll ◽  
E. S. Furfine ◽  
D. P. Cohen ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Single Agent ◽  
Angiogenesis Inhibitor ◽  
Maximum Tolerated Dose ◽  
Vegf Receptor ◽  
Advanced Solid Tumors ◽  
Grade 3 ◽  
Ecog Ps ◽  
Dose Levels ◽  
Vegf Trap

13061 Background: VEGF Trap is a potent angiogenesis inhibitor comprising portions of human VEGF receptor VEGFR1 (Flt-1) and VEGFR2 (KDR) extracellular domains fused to the Fc portion of human IgG. VEGF Trap binds VEGF and neutralizes all VEGF-A isoforms plus placental growth factor. FOLFOX4 is an approved chemotherapy regimen for the treatment of colorectal cancer. This study was designed to evaluate the safety and pharmacokinetics (PK) of VEGF Trap plus FOLFOX4 administered intravenously. Methods: Successive cohorts of 3–6 patients (pts) with advanced solid tumors received intravenous VEGF Trap plus FOLFOX4 every 2 weeks. Study endpoints included safety, PK, and immunogenicity. Antitumor activity was assessed by CT scan. Results: Six pts (3 male/3 female), median age 55 (25–74), ECOG PS 0/1/2: 2/4/0, with a variety of advanced solid tumors, including 2 gastric and 2 neuroendocrine tumors, have received a total of 19 cycles of VEGF Trap plus FOLFOX4 across 2 VEGF Trap dose levels (2.0 mg/kg, 4.0 mg/kg) to date. Three of these 6 pts had grade 3 AEs (hypertension [n=2], neutropenia [n=2]), which were manageable and reversible. However, no dose-limiting toxicities or grade 4 AEs have been encountered so far. Preliminary mean free VEGF Trap clearance was 17.1 mL/kg/day. No pts have developed anti-VEGF Trap antibodies. Conclusions: VEGF Trap may be safely combined with FOLFOX4 at the dose levels studied. Preliminary free VEGF Trap clearance did not differ significantly from that seen with single-agent exposure; chemotherapy PK analysis is pending. The maximum tolerated dose has not yet been reached, and dose escalation continues. Updated safety, pharmacokinetic, and preliminary efficacy results from this ongoing study will be presented. [Table: see text]

Phase I/II study of sorafenib and temsirolimus for patients with recurrent glioblastoma (GBM) (NABTC 05–02)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2006-2006 ◽  
Author(s):  
P. Y. Wen ◽  
T. Cloughesy ◽  
J. Kuhn ◽  
K. Lamborn ◽  
L. E. Abrey ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Single Agent ◽  
Recurrent Glioblastoma ◽  
Molecular Therapy ◽  
Dose Finding ◽  
Pharmacokinetic Data ◽  
Eligibility Criteria ◽  
Grade 3 ◽  
Recurrent Gbm

2006 Background: The activity of targeted molecular therapy with single agents has been disappointing in GBM. Combination therapy simultaneously targeting both the PI3k/Akt/mTOR and the MAP kinase pathway may be more effective. Methods: The North American Brain Tumor Consortium conducted a phase I/II study of sorafenib (VEGFR/PDGFR/Raf inhibitor) in combination with temsirolimus (mTOR inhibitor) in recurrent GBM. Eligibility criteria included histologically proven GBM, radiologic progression, > 18 years old, KPS > 60, adequate bone marrow reserve, and organ function. There was no limit on the number of prior relapses for phase I and no more than two prior relapses for phase II. No enzyme-inducing antiepileptic drugs were allowed. Dose-finding used a standard 3 + 3 design with the MTD defined as the dose with DLTs in 1/6 or fewer patients. The primary endpoint for the phase II component was PFS6 (p0 = 15%; p1 = 35%). A 2-stage design was used. If > 4 of the initial 19 patients achieved PFS6, an additional 14 patients would be accrued for a total of 33 patients. Results: In phase I, 13 patients were enrolled. Median age was 50 years (32–59); median prior chemotherapy 1 (1–3). The initial doses were sorafenib 200 mg bid and temsirolimus 25 mg intravenously once weekly. The MTD was 400 mg bid of sorafenib daily combined with 25 mg of temsirolimus weekly. At this dose 1/6 patients had a DLT (grade 3 thrombocytopenia). Other grade 3 or 4 toxicities included transaminitis, hypophosphatemia, fatigue, diarrhea, and hyperlipidemia. Pharmacokinetic data were similar to that for single agent sorafenib and temsirolimus suggesting that there were no significant interaction between the two drugs. In phase II, 19 patients were accrued to stage I. Median age 50 years (24–64); median prior relapses 1 (range 1–2). One patient was found not to have GBM on central review. No patient remained progression free at 6 months, although two patients stopped treatment prior to 26 weeks for other than progression (alternative therapy, cerebral ischemia). As result, the study was terminated and did not proceed to the second stage. Conclusions: The combination of sorafenib and temsirolimus was moderately well-tolerated but did not demonstrate sufficient efficacy in recurrent GBM to warrant further investigation. 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.

Trisenox® (arsenic trioxide) in Patients with Myelodysplastic Syndromes (MDS): Preliminary Results of a Phase I/II Study.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1433-1433
Author(s):  
Norbert Vey ◽  
Francois Dreyfus ◽  
Agnes Guerci ◽  
Pierre Fenaux ◽  
Herve Dombret ◽  
...  
Keyword(s):  
Phase I ◽  
Arsenic Trioxide ◽  
Lower Risk ◽  
Single Agent ◽  
Clinical Activity ◽  
Molecular Response ◽  
Improvement Rate ◽  
Preliminary Results ◽  
Duration Of Response ◽  
Grade 3

Abstract Introduction: Single-agent Trisenox® (arsenic trioxide) induces high hematologic and molecular response rates leading to prolonged survival in patients with relapsed/refractory acute promyelocytic leukemia. Arsenic trioxide exhibits multifaceted mechanisms of action, including induction of tumor cell differentiation, apoptosis, and angiogenesis inhibition. Recent reports have documented the clinical activity of arsenic trioxide in MDS patients, leading to improvements in hematologic parameters and to transfusion independence or reduction. We report preliminary results of an ongoing European multicenter phase I/II study of arsenic trioxide in MDS patients. Patient eligibility includes all FAB categories with &lt;30% blasts. Final results of the study will be reported. Methods: Arsenic trioxide is given as a 1-hr IV infusion, loading dose of 0.30 mg/kg/day for 5 days, and maintenance with 0.25 mg/kg/day 2X a week for &gt;15 weeks. Disease assessments are every 8 weeks, by modified IWG response criteria. Patients: 105 patients have been enrolled: median age is 67 years (range 31–89), median time from diagnosis to 1st dose is 10.9 months (range 0.2–117.6). 101 patients have received drug and have been evaluated (78M/23F). 39 patients have IPSS lower-risk (LR: low and Int-1) and 62 have higher-risk (HR: high and Int-2) MDS. FAB categories are RA (9 patients), RARS (11), RAEB (62), RAEB-t (13), and CMML (6). 86 patients were transfusion dependent at baseline. Results: Responses were observed in 27 evaluable patients (27%). They include 1 CR (1%), 20 major Hematologic Improvements (HI: 20%) and 6 minor HI (6%). Responses were seen across the 3 lineages: major HI-Erythroid: 11; major HI-Neutrophil: 8 (including 2 also HI-E); and major HI-Platelet: 6 (including 3 also HI-E). The hematologic improvement rate among LR patients was 9/39 (23%) and among HR patients, 18/62 (29%, including the CR). 14 patients became transfusion independent and an additional 7 patients had transfusions reduced by ≥50%. Responses were seen after 1–3 months of treatment, and median duration of response is 4+ months at this time. The true duration of response is not yet known, as 20 patients were still responding at their most recent assessments. Arsenic trioxide toxicity was manageable and mostly mild; 4 patients had treatment-related grade 3 febrile neutropenia and 1 patient each experienced grade 3 and grade 4 thrombocytopenia. One had grade 4 neutropenia; the only other grade 4 toxicity was 1 pulmonary edema. An additional 14 patients each had a different grade 3 event. QTc prolongation was reported in only 1 patient, who had 2 isolated episodes that were considered clinically insignificant and did not result in treatment delay. No patient had alopecia or severe nausea or vomiting. Summary and Conclusions: These preliminary results indicate that arsenic trioxide is generally well tolerated, even by elderly patients, and that it induces responses in all three hematopoietic lineages, in similar proportions of patients with higher risk and with lower risk MDS. 14 of 86 transfusion-dependent patients became transfusion independent. Final results of the study will be presented.

A Phase I/II Study of Bortezomib and Low Dose Intravenous Melphalan (BM) for Relapsed Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2555-2555 ◽  
Author(s):  
Rakesh Popat ◽  
Heather E. Oakervee ◽  
Nicola Foot ◽  
Samir Agrawal ◽  
Patricia Smith ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Progressive Disease ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Median Number ◽  
Overall Response ◽  
Grade 3 ◽  
Number Of Cycles

Abstract Background: Bortezomib as a single agent has known efficacy in the treatment of relapsed multiple myeloma. The overall response rate (CR+PR+MR) was 35% in the SUMMIT study and 46% in the APEX study. In-vitro studies including our own have demonstrated potent synergy with other chemotherapeutic agents such as melphalan. It therefore follows that responses to bortezomib may be further improved by the combination of such drugs. Aims: The primary objectives of this Phase I/II study was to assess the safety, tolerability and response rates in patients with relapsed multiple myeloma; secondary objectives being time to progression (TTP) and overall surival (OS). Methods: This was a multi-centre, non-randomised trial for patients with relapsed myeloma. Patients received bortezomib 1.3mg/m2 on days 1,4,8 and 11 of each 28 day cycle with melphalan on day 2 at increasing dose levels. This was initially at 10mg/m2, but due to cytopenias subsequently at 2.5 and 5mg/m2 (levels 1a, 1 and 2) and we plan to escalate to 7.5mg/m2. Up to 8 cycles were given with dexamethasone added for stable or progressive disease after 4 or 2 cycles respectively. Responses were determined by EBMT criteria. Results: To date, 18 patients have been enrolled (12 male 6 female; median age 60 [range 44–73]; median number of prior therapies 3 [range 1–5] of which 17 have had at least one autologous stem cell procedure with high dose melphalan; 10 prior thalidomide and 2 prior bortezomib). 12 patients received melphalan at 10mg/m2 but due to unacceptable delays predominantly due to thrombocytopaenia, subsequent treatment levels commenced at 2.5mg/m2. The median number of cycles completed thus far is 4 (range 0–8) and of the 16 evaluable, the overall response rate (CR+PR+MR) across all treatment levels was 50% rising to 75% following the addition of dexamethasone as per protocol. At level 1a (melphalan 10mg/m2 ,N=12, median number of cycles completed =5) the best responses (with dexamethasone as indicated) were: 1CR, 1 VGPR, 5 PR, 2 MR; at level 1 (melphalan 2.5mg/m2, N=4) 1 PR, 2 MR (after 2 cycles only). The median time to any response was 1 cycle (range 1–3 ). Three patients have progressive disease, but the median TTP and OS have not yet been reached (median follow-up 3 months). Non-haematological toxicities have been modest with 7 SAEs reported of which only 1 was possibly drug related (myocardial infarction), and 4 episodes of Grade 3 neuropathy (2 resulting in study withdrawal). The commonest grade 3–4 haematological toxicity was thrombocytopaenia (N=10) complicated by bleeding in one patient, followed by neutropenia (N=6). Summary: The combination of bortezomib and intravenous melphalan can be given safely to patients with relapsed multiple myeloma and dose escalation is ongoing. Myelosupression was the commonest grade 3–4 adverse event. A response rate of 50% was seen, which was further improved to 75% with the addition of dexamethasone. This combination may therefore result in higher responses than single agent bortezomib in heavily pretreated patients.

Results of a Phase I Trial of SGN-40 (Anti-huCD40 mAb) in Patients with Relapsed Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3576-3576 ◽  
Author(s):  
Mohamad A. Hussein ◽  
James R. Berenson ◽  
Ruben Niesvizky ◽  
Nikhil C. Munshi ◽  
Jeffrey Matous ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Aseptic Meningitis ◽  
Dose Escalation ◽  
Single Agent ◽  
Objective Response ◽  
Lymphocytic Leukemia ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Grade 3

Abstract SGN-40 is a humanized anti-CD40 monoclonal antibody that has demonstrated potent in vitro and in vivo efficacy against cell lines expressing CD40, a member of the tumor necrosis factor receptor family. CD40 is widely expressed on tumors of B-cell origin, including myeloma, non-Hodgkin’s lymphoma, Hodgkin’s disease, and chronic lymphocytic leukemia. SGN-40 has been evaluated in a phase I, multi-dose, single-agent, dose escalation study for patients with relapsed or refractory multiple myeloma. This single-arm trial was designed to evaluate safety, pharmacokinetics, immunogenicity, and antitumor activity. Thirty-two patients were treated at five clinical sites. Patients had been heavily pretreated with a median of four prior regimens and 4.8 years since diagnosis. Initially, patients were treated with four weekly infusions at a cohort-specific dose. This schedule was well-tolerated at 0.5, 1.0 and 2.0 mg/kg/wk; however, two of three patients experienced dose-limiting toxicities following the first dose at 4 mg/kg. One patient had aseptic meningitis (grade 3) and another had headache (grade 3) and aseptic meningitis (grade 4); both patients fully recovered after several days of symptom management. Subsequently, the protocol was amended to allow intra-patient dose-loading, which resulted in successful dose escalation to 8 mg/kg, the highest dose tested. There was neither recurrence of grade 3 neurotoxicity nor evidence of cumulative toxicity. Drug-related adverse events were mostly grade 1 or 2 and included: fatigue (38%), headache (34%), nausea (16%), conjunctivitis (13%), diarrhea (13%), vomiting (13%), anemia (9%), anorexia (9%), chills (9%), and pyrexia (9%). Transient grade 3 elevation of hepatic transaminases (1) and grade 3 neutropenia (1) were observed. Overall, toxicity did not appear to increase in incidence or severity at higher doses. Patients were evaluated at baseline and end of treatment for development of anti-SGN-40 antibodies. Of 30 patients for whom appropriate samples were available for testing, only one low-titer immune response (16 ng/mL) was detected, suggesting that immunogenicity does not appear to be a significant problem in this patient population. Pharmacokinetic analysis demonstrates dose-proportional changes in Cmax and AUC with a relatively short terminal half-life, similar to that seen in non-human primates. Final analysis of SGN-40 serum levels is ongoing. Although several patients demonstrated decreased M-protein and improvement in subjective symptoms, no patients met criteria for objective response. Five patients (16%) had stable disease at the time of restaging. In summary, dose-dependent toxicity was established only in relation to the first dose of SGN-40, which may be due to partial agonistic signal transduction. Using a dose-loading schedule, SGN-40 was administered up to 8 mg/kg without reaching a maximum tolerated dose. Some patients with advanced myeloma appeared to derive clinical benefit from therapy, and further development of this antibody, either as monotherapy or in combination with other anti-myeloma therapies, is indicated.

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

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