A Phase I, Multi-Dose, Dose Escalation Study of SGN-40 (anti-huCD40 mAb) in Patients with Refractory or Recurrent Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2413-2413
Author(s):  
Mohamad A. Hussein ◽  
Ruben Niesvizky ◽  
Nikhil Munshi ◽  
James C. Berenson ◽  
Kenneth C. Anderson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Escalation ◽  
Transmembrane Protein ◽  
M Protein ◽  
Type I ◽  
Antitumor Effects ◽  
Grade 3 ◽  
Dose Levels

Abstract CD40 is a type I transmembrane protein that upon binding to CD40 ligand regulates important biologic effects in the immune system. CD40 is also highly expressed on hematologic tumors, which has raised interest in the potential for its use as a tumor target for antibody-based cancer therapy. SGN-40 is a humanized monoclonal antibody that selectively binds to human CD40 and induces apoptosis and growth inhibition of a wide variety of B-cell derived cancer cell lines in vitro. Our preclinical work has confirmed the in vitro cytotoxicity of SGN-40 against human multiple myeloma (MM) cells via several mechanisms. These include induction of cytotoxic ligands of TNF superfamily; suppression of IL-6-induced proliferative and anti-apoptotic effects, as well as antibody-dependent cell-mediated cytotoxicity (Tai, et al, Cancer Research64, 2846–2852, April 15, 2004). Since ≥ 90% of MM cells express CD40, targeting CD40 using SGN-40 presents a potential novel treatment strategy. Based on these preclinical data, a phase I study is being conducted to define the toxicity profile, characterize the pharmacokinetics (PK), and evaluate antitumor effects of SGN-40 in patients with refractory or recurrent MM. Four weekly doses ranging from 0.5 to 16 mg/kg are planned to be administered to groups of at least three patients per cohort. Patients will be followed for up to 6 weeks post their last dose. Currently, a total of seven patients have been treated with SGN-40 at dose levels of 0.5 and 1.0 mg/kg. No grade 3 or 4 non-hematologic dose limiting toxicities have been observed. One patient experienced a transient Grade 3 decrease in hemoglobin. Decrease in CD19 positive B-cells were noted for patients treated at both dose levels. Changes in serum and urine M protein levels were measured to estimate potential anti-tumor effects of SGN-40. Of the seven patients evaluated, one patient at 0.5 mg/kg dose had stable disease, based on serum M protein, over the 10 week study period. Clinical evaluation with dose escalation of this agent continues and updated safety, PK and antitumor data will be presented.

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.

Bortezomib in Combination with Melphalan in the Treatment of Relapsed or Refractory Multiple Myeloma: A Phase I/II Study.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 209-209 ◽  
Author(s):  
James Berenson ◽  
H. Yang ◽  
R. Swift ◽  
K. Sadler ◽  
R. Vescio ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Escalation ◽  
De Novo ◽  
Optimal Dose ◽  
Fixed Dose ◽  
Full Potential ◽  
Dose Escalation Study ◽  
Refractory Multiple Myeloma

Abstract Introduction: Bortezomib (VELCADE®) is a proteasome inhibitor that has demonstrated durable responses as monotherapy for the treatment of pts with relapsed and refractory multiple myeloma. In vitro, bortezomib has been shown to restore melphalan sensitivity to melphalan-resistant cell lines (U266-LR7) and to synergize with melphalan in killing myeloma cells, thereby allowing the use of lower concentrations of melphalan (Ma et al, Clin Cancer Res.2003;9:1136). The objective of this dose-escalation phase I/II study was to determine an optimal dose of combination bortezomib + melphalan, starting with doses below those usually recommended for each agent for pts with refractory or relapsed multiple myeloma. Dose limiting toxicities, safety, tolerability, and activity were assesed in a dose-escalation study. Methods : Bortezomib 0.7 mg/m2 was administered by IV push on days 1, 4, 8, and 11 in combination with oral melphalan (0.025, 0.05, 0.1, 0.15, 0.25 mg/kg) on days 1–4 every 4 weeks for up to 8 cycles to 3-pt cohorts with active progressive disease. In the absence of dose-limiting toxicity (DLT), bortezomib was increased to 1.0 mg/m2 and melphalan co-administered using the original 5 escalating doses to subsequent cohorts. Results : Twenty six pts (50% male, median age 55 years, range 33–90 years) have been accrued to the study. The myeloma subtypes include IgG (16/26), IgA (4/26), IgM (2/26) and light chain only (4/26). The median ß2 microglobulin level was 5.0 mg/L (range 2.2–14 mg/L). In this heavily pretreated population (range 2–7 prior therapies), 12 patients received prior melphalan, 12 prior thalidomide, 7 prior CC-5013, 13 prior VAD, 2 prior bortezomib, and 8 prior autologous stem cell transplantation. Dose escalation has proceeded into the bortezomib 1.0 mg/m2 + melphalan 0.10 mg/kg cohort. Toxicities have been manageable. One DLT, grade 4 anemia, was observed at bortezomib 1.0 mg/m2 + melphalan 0.025 mg/kg, requiring expansion of that specific cohort. Grade 3 events were predominantly associated with myelosuppression (anemia, neutropenia, and thrombocytopenia) and were observed only among pts with baseline cytopenia. Among the 12 pts with baseline peripheral neuropathy (PN), symptoms worsened transiently in 1 pt, resolved in 1 pt, and remained stable in the other pts. Treatment-related PN (grade 1) developed de novo in 2 pts. Responses were observed in 67% (16/24 evaluable) of pts: 1 CR, 1 near CR, 6 PR, and 8 MR. The CR and near CR occurred in pts receiving bortezomib 1.0 mg/m2 in combination with melphalan .025 mg/kg. PR or better was independent of prior type of therapy and was also observed among pts who had previously received melphalan or bortezomib. Median time to progression was 1-18 mo. Six active pts out of 26 total pts remain progression-free for 2-8+ mo. Conclusion : Combination bortezomib plus oral melphalan is a promising regimen for the treatment of relapsed, refractory myeloma. The responses that were observed in pts who had previously received either drug serve as preliminary confirmation of preclinical evidence that the combination of low-dose bortezomib and melphalan has the capacity for chemosensitization and suggest possible synergy. Dose escalation with melphalan plus a fixed dose of bortezomib 1.0 mg/m2 is continuing in order to explore the full potential of this combination.

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.

Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1723-1723
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Peter Anglin ◽  
Christine Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Oral Cyclophosphamide ◽  
Varicella Zoster ◽  
Refractory Multiple Myeloma ◽  
Grade 3 ◽  
Dose Levels

Abstract Oral cyclophosphamide and prednisone is a convenient regimen in relapsed and refractory multiple myeloma (MM), with a partial response (PR) rate of 40% and median progression-free survival of 19 months in our retrospective analysis of patients in first or second relapse after autologous stem cell transplantation (ASCT) (Trieu Y, et al, Mayo Clin Proc2005; 80: 1582). We sought to enhance the efficacy of this regimen by adding oral lenalidomide (Revlimid®), a potent anti-myeloma agent, in a phase I-II trial. The CPR regimen consisted of cyclophosphamide on days 1, 8 and 15, lenalidomide on days 1–21, and prednisone 100 mg every other day in a 28-day cycle. ASA 81 mg/day was given to all patients (pts) as prophylaxis for DVT. Three dose levels were evaluated using a 3 by 3 dose escalation design. Between 11/2007–07/2008, 15 pts with relapsed/refractory MM were entered onto study. Median age was 60 (45–78) years and 60% were male. Immunoglobulin subtype was IgGκ:λ in 10:1; IgA κ:λ in 2:1 and κ light chain in 1. Median number of prior regimens was 2 (1–3) and 14 had undergone previous ASCT, including double transplants in 2 pts. Prior therapy also included thalidomide in 3 (20%) and bortezomib in 6 (40%). FISH cytogenetics were available in 9, but none had 13q deletion, t(4;14) or p53 deletion. At the time of protocol entry, median β2-microglobulin level was 222 (92–325) nm/L, albumin 38 (35–46) g/L, creatinine 78 (50–100) μmol/L, platelet count 230 (93–318) x 109/L and ANC 2.5 (1.9–9.0) x 109/L. Protocol treatment is summarized in Table 1. Dose level N Cyclophosphamide dose (mg/m2) Lenalidomide dose (mg) Prednisone dose (mg) Median # cycles given 1 3 150 15 100 9 2 3 150 25 100 6 3 6 300 25 100 4 3 (expanded) 3 300 25 100 1 Dose limiting toxicity was not observed during cycle 1 at any of the dose levels and the maximum tolerated dose of this regimen has not yet been reached at the highest dose level planned; all pts remain on active therapy. Grade 3/4 thrombocytopenia was seen in 1 pt (cohort 2) and neutropenia in 4 pts (1 in cohort 1, 1 in cohort 2 and 2 in cohort 3) and were managed with dose reduction and/or growth factor support. No episodes of febrile neutropenia occurred in any pt. Only 1 pt experienced varicella zoster; routine antiviral prophylaxis was not used. Other grade 3/4 non-hematologic toxicities were uncommon and included abdominal pain/bacteremia in 1 pt in cohort 1, hypokalemia in 1 pt in cohort 2, and DVT in 1 pt in cohort 3. Mild grade 1/2 constipation (47%), muscle cramps (33%) and fatigue (33%) were also noted. To date, best response includes the following: dose level 1 (1 near complete remission [nCR], 2 PR); dose level 2 (3 PR); dose level 3 (4 PR, 2 minimal response [MR]); expanded cohort 3 (1 MR, 2 too early). We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28-day cycle with minimal toxicity; 2) the overall response rate (nCR + PR + MR) in 13 evaluable pts to date is 87%; 3) no pts have progressed in this preliminary analysis; 4) longer follow-up is required to assess the long-term efficacy of this regimen.

Phase I Study of a Liposomal Carrier (CPX-351) Containing a Synergistic, Fixed Molar Ratio of Cytarabine (Ara-C) and Daunorubicin (DNR) in Advanced Leukemias

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2984-2984 ◽  
Author(s):  
Eric J. Feldman ◽  
Jeffrey Lancet ◽  
Jonathan E. Kolitz ◽  
Ellen Ritchie ◽  
Alan F. List ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Dose Escalation ◽  
Phase I Study ◽  
Molar Ratio ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Grade 3 ◽  
Refractory Aml

Abstract Background: CPX-351 is a liposomal formulation of Ara-C and DNR which fixes the synergistic 5:1 molar ratio found to enhance efficacy in both in vitro and in vivo preclinical leukemia models. CPX-351 overcomes the pharmacokinetic (PK) differences of each drug, enabling the maintenance of the 5:1 molar ratio for extended periods of time after IV administration and the delivery of this ratio to bone marrow. Preclinical data from in vitro models show that CPX-351 is actively internalized by leukemic cells within vacuoles and subsequently releases DNR intracellularly. A Phase I study was performed with CPX-351 in patients with acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), and myelodysplastic syndrome (MDS). Objectives: to determine safety, tolerability, and pharmacokinetics of a 90 min IV infusion of CPX-351 given on days 1, 3, 5 to patients with advanced leukemia and MDS, and to seek preliminary evidence of antitumor activity. Methods: Patients with relapsed/refractory AML/ALL and MDS were eligible. A second induction course was permitted if the day 14 bone marrow showed evidence of antileukemic effect and persistent leukemia. Dosing started at 3 units/m2 (1 u = 1 mg Ara-C and 0.44 mg DNR) using single patient cohorts and dose doublings. Three patient cohorts and 33% dose increments began after evidence of antileukemic activity and continued until limiting toxicities (DLTs) completed dose escalation. PK samples were collected after each dose. Results: Forty-seven subjects received 69 courses of CPX-351: Male/Female = 31/16, median age = 62 years (range 23–81); 44 patients had AML and 3 patients had ALL; median number of prior regimens = 2 (1–7). Thirty-seven patients entered the escalation phase of the study and ten subjects, most in first relapse, were treated after completion of dose escalation to confirm safety. At 24 u/m2 antileukemic effects were observed leading to increased cohort size to 3 and decreased escalation rate to 33%. The MTD and recommended Phase 2 dose was 101 u (101 mg Ara-C + 44 mg DNR)/m2 after observing 3 DLTs (decreased LVEF, hypertensive crisis, prolonged aplasia) at 134 u/m2. Adverse events data are available for 36 of 37 patients from the escalation phase of the study. Nonhematologic grade 3–5 toxicities occurring in more than one patient included: infections (58%), dyspnea (11%), fever (11%), hypophosphatemia (8%), hypokalemia (6%), renal failure (6%), skin rash (6%), headache (6%) hyperglycemia (6%) hypoxia (6%) and respiratory failure (6%). Mucositis of any grade was observed in 42% of patients with 3% having grade 3 mucositis. Diarrhea of grade 1 and 2 severity occurred in 39% of patients. Interim analysis of PK data demonstrates maintenance of the 5:1 molar ratio and detectable encapsulated drug persisting up to 24 hours. The average half-lives were 35 hr for total Ara-C and 23 hr for DNR, significantly longer than reported for the conventional drugs. Overall, 11 patients achieved CR/CRp. Among the 19 patients treated at the MTD, 5 of the 13 patients evaluable for response achieved CR. Six patients were treated above the MTD (134 u/m2) and 2 achieved CR. Median time to CR was 43 days. Conclusions: The recommended phase 2 dose is 101 u/m2. CPX-351 was well tolerated, with no unexpected toxicities noted up to the MTD. GI toxicities and mucositis were transient and nearly always of mild to moderate severity. Reduced LV function was observed in two patients both with substantial prior anthracycline exposure. CRs were observed in heavily pre-treated patients with relapsed/refractory AML. Future plans include a randomized Phase 2 study comparing CPX-351 versus Cytarabine + Daunorubicin (“7 + 3”) in older (>60 yo) subjects with previously untreated AML, and a phase 2 study in patients with AML in 1st relapse.

Clinical Activity of a Novel Multiple Tyrosine Kinase and Aurora Kinase Inhibitor, ENMD-2076, Against Multiple Myeloma: Interim Phase I Trial Results

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1957-1957 ◽  
Author(s):  
Sherif Farag ◽  
Shuhong Zhang ◽  
Attaya Suvannasankha ◽  
Jing Liang ◽  
Robyn O'Bryant ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Phase I Clinical Trial ◽  
M Protein ◽  
High Dose ◽  
Significant Activity ◽  
Dose Levels ◽  
Asymptomatic Elevation

Abstract Abstract 1957 Background: Despite recent improvements, MM remains incurable, indicating the need for continued investigation of novel agents. ENMD-2076 is a novel, orally active molecule that has been shown to have significant activity against Aurora and multiple receptor tyrosine kinases. Recently, we demonstrated that ENMD-2076 has significant pre-clinical in vitro and in vivo activity against MM cell lines and primary myeloma cells (Wang et al., Br J Haematol, 2010). Furthermore, ENMD-2076 inhibited critical pathways for MM cell survival and proliferation, including PI3K/AKT pathway with downregulation of survivin and XIAP, and Aurora A and B kinases, inducing G2/M cell cycle arrest, angiogenesis, and the FGFR3 pathway. We present the interim results of a phase I clinical trial of ENMD-2076 in patients with relapsed and refractory MM. Methods: An open label, single agent, dose-escalation dose safety and tolerability trial of ENMD-2076 is currently conducted in heavily pre-treated, relapsed and refractory MM patients who have previously failed standard therapy. Using a 3+3 design, dose escalation with ENMD-2076 is currently being studied at the doses: 150, 225, 325, 400 mg PO daily in 28 day cycles. Patients receive 28-day cycles according to safety and tolerability and absence of progression. Pharmacokinetics and pharmacodynamic studies, including effect on phosphorylated histone 3 (pH3) in purified bone marrow MM cells, effect on the PI3K pathway in peripheral blood mononuclear cells (PBMC), and circulating endothelial cell precursors are being investigated. Results: Currently, dose-escalation for the first three dose levels has been completed. Nine patients of median age 54 (range, 48–76) years were treated. There were 5 males and 4 females. The median number of prior regimens was 3 (range, 2–5), with 8 patients having failed high-dose melphalan and autologous stem cell transplantation. The most commonly observed toxicities included grades 1–2 anorexia (n=2), nausea (n=2), diarrhea (n=3), fatigue (n=3), asymptomatic elevation of amylase (n=3) and lipase (n=1), leucopenia (n=1), and heavy proteinuria (n=1). Grades 3 toxicities included hypertension (n=1), asymptomatic elevation of lipase (n=2), and thrombocytopenia (n=1). No dose-limiting toxicity was observed with all toxicities resolving promptly upon interruption or discontinuation of dosing. All patients treated on dose level 1 had progression of disease on treatment, 1 patient in dose level 2 had stabilization of disease, and 2 patients on dose level 3 had stable disease although with 21% and 19% reduction in serum M-protein after the first cycle. Significant increases in pH3 in MM cells were observed in 4 of 5 patients tested in dose levels 2 and 3. p-STAT3 and pGSK-beta were downregulated in PBMC in one patient, who also had a 19% reduction in M-protein. Conclusion: In the ongoing phase I clinical trial, ENMD-2076 appears safe and well –tolerated at the doses tested to date. Additional schedules are under investigation based on tolerability and correlative analyses. ENMD-2076 may hold promise as a treatment for MM and further study is warranted. Disclosures: Farag: EntreMed, Inc: Research Funding. Bray:EntreMed, Inc.: Employment. Sidor:EntreMed, Inc: Employment.

Results of A Phase I Study of Milatuzumab, a Humanized Anti-CD74 Antibody, and Veltuzumab, a Humanized Anti-CD20 Antibody, In Patients with Relapsed and Refractory B-Cell Non-Hodgkin's Lymphoma,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3707-3707
Author(s):  
Beth Christian ◽  
Lapo Alinari ◽  
Jeffrey A. Jones ◽  
Don M Benson ◽  
Joseph M. Flynn ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Cell Lymphoma ◽  
Prior Therapy ◽  
Infusion Reactions ◽  
Cd20 Antibody ◽  
Grade 3 ◽  
Anti Cd20 ◽  
Dose Levels

Abstract Abstract 3707 Background: Preclinical studies conducted at our institution (Alinari et al. Blood. 2011;117:4530–41) demonstrated superior efficacy of milatuzumab (Immunomedics, Inc.), a humanized anti-CD74 antibody, in combination with rituximab in vitro and in an in vivo preclinical model of mantle cell lymphoma (MCL), compared to either agent alone. Veltuzumab (Immunomedics, Inc.), a humanized anti-CD20 antibody, has been reported to have several advantages over rituximab including slower off-rates, shorter infusion times, higher potency, and improved therapeutic responses in animal models. As a result of the anti-tumor activity observed in vitro with combined veltuzumab and milatuzumab, we initiated a phase I/II trial in pts with relapsed or refractory B-cell NHL after at least 1 prior therapy to determine the safety, tolerability, and overall response rate with this combination. Methods: Pts received veltuzumab 200 at mg/m2 weekly combined with escalating doses of milatuzumab at 8, 16, and 20 mg/kg twice per wk of wks 1–4, 12, 20, 28, and 36. All pts received premedication with acetaminophen, diphenhydramine, hydrocortisone 50 mg, and famotidine prior to veltuzumab and milatuzumb doses. Dose limiting toxicity (DLT) was defined during weeks 1–4. Although not defined as DLT, 3 of the first 6 pts enrolled at dose levels 1–2, had significant grade 3 infusion reactions with milatuzumab. The study was amended to separate veltuzumab and milatuzumab dosing days and add 20 mg dexamethasone immediately prior to and 10 mg post-milatuzumab. Enrollment resumed with 3 additional pts at dose levels 1 and 2 in order to determine if tolerability was improved. Results: The phase I study has completed enrollment with 18 pts (follicular NHL grade 1–2 n=5; grade 3 n=5; transformed follicular n=1; diffuse large B-cell lymphoma (DLBCL) n=4; marginal zone lymphoma (MZL) n=1; MCL n=1; and lymphoplasmacytic lymphoma n=1) that have completed at least 4 weeks of combination therapy. Median age was 65 years (range 44–81), and pts received a median of 3 prior therapies (range 1 – 9), including 3 pts who had undergone prior autologous stem cell transplant. Ten of 18 (56%) pts were refractory to rituximab defined as having less than a partial response to the last rituximab-containing regimen. No DLTs were observed, and no pts experienced grade 3 infusion reactions after the protocol was modified. Other grade 3–4 toxicities at least possibly related to protocol therapy consisted of lymphopenia (n=8, 44%), fatigue (n=2, 11%), neutropenia (n=1, 6%), hyperglycemia (n=1, 6%), and anemia (n=1, 6%). Grade 1–2 infections (n=5, 27%) included thrush, sinusitis, and pneumonia with no pts requiring dose delays or hospitalization. Other frequently observed grade 1–2 toxicities were transient hyperglycemia (n=12, 66%), thrombocytopenia (n=11, 61%), reversible infusion reactions (n=9, 50%), fatigue (n=8, 44%), leukopenia (n=8, 44%), and anemia (n=7, 39%). Human anti-veltuzumab and anti-milatuzumab antibodies, collected pretreatment and day 1 of weeks 4, 12, and 36, have not been detected in any pt. Pharmacokinetic data available from 16 pts through week 10 indicated mean plasma veltuzumab and milatuzumab concentrations immediately post-infusion were 108 ± 7 and 296 ± 22 μg/mL, and mean trough levels were 47 ± 7 and 3 ± 0.3 μg/mL, respectively. All 18 pts were assessable for response at wk 5 with 5 pts currently remaining on active therapy and 4 pts completing treatment through wk 36. To date, complete response was observed in 1 pt with grade 1–2 follicular NHL (3 prior therapies) who was rituximab-refractory and ultimately underwent allogeneic transplant. Partial responses were observed in 3 pts; 2 with grade 3 follicular NHL refractory to rituximab (3 prior therapies including autologous transplant and 5 prior therapies, respectively) and 1 with MZL (1 prior therapy). All responding pts achieved response following induction therapy. Stable disease was observed in 10 pts; of these pts, 6 pts had SD of a median duration of 6 months (range 2.5–10 months) and 4 remain on active therapy. Conclusions: Combination therapy with veltuzumab and milatuzumab was well-tolerated in a population of heavily pre-treated pts with relapsed or refractory NHL. 14/18 pts had evidence of antitumor activity with 22% having an objective overall response, including rituximab-refractory pts. Disclosures: Christian: Immunomedics, Inc.: Research Funding. Off Label Use: Veltuzumab and milatuzumab in non-Hodgkin's lymphoma is off-label drug use. Wegener:Immunomedics, Inc.: Employment, Management and Stock / Stock-options. Goldenberg:Immunomedics, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Escalated Dose Bortezomib Once Weekly Combined with Lenalidomide and Dexamethasone (eVRD) Followed by Lenalidomide Maintenance in First Relapse of Multiple Myeloma (MM). the HOVON 86 Phase 2 Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1853-1853
Author(s):  
Pieter Sonneveld ◽  
Okke de Weerdt ◽  
Mark-David Levin ◽  
Wendimagegn Ghidey ◽  
Edo Vellenga ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 2 ◽  
Level 3 ◽  
First Relapse ◽  
Grade 3 ◽  
Dose Levels

Abstract Abstract 1853 Background: Bortezomib (1.3 mg/m2) combined with Lenalidomide (10–25 mg) and Dexamethasone (VRD) is effective in newly diagnosed and relapsed multiple myeloma (MM). Reported data on the effect of these drugs in relapse/refractory MM are available from the APEX and MM-009/MM-010 trials, respectively. These trials, however, were performed in patients with 2–8 prior regimens. Aim: This investigator sponsored two-step phase 2 HOVON trial was designed to evaluate escalated dosages of Bortezomib (B) given once weekly and daily Lenalidomide (L) combined with weekly Dexamethasone (D) (eVRD) followed by Lenalidomide maintenance in an homogenous group of patients with symptomatic MM in first relapse. The goal was to explore the maximum tolerated dose of this combination in order to achieve a durable second remission. Methods: Dose levels were B 1.3 mg/m2, L 10 mg, (level 1); B 1.6 mg/m2, L 10 mg (level 2); B 1.6 mg/m2, L 15 mg (level 3); B 1.6 mg/m2, L 20 mg (level 4). D dose was 20 mg days 1–2, 8–9, 15–16 in all dose levels. Inclusion criteria were symptomatic MM ISS stage 1–3, aged 18–80 in first relapse after initial treatment. The primary endpoint was response (complete response (CR) according to IMWG criteria, very good partial response (VGPR), partial response (PR), together overall response (ORR)) with Progression-free Survival (PFS), overall survival (OS) and toxicity as secondary endpoints. Results: Eighty-one patients were included, i.e. 15 patients in dose levels 1, 2 and 3, followed by 66 in the phase 2 part. This report is based on 12 patients in the dose escalation phase and the first 42 patients in the phase 2 part. Median age was 67 yrs, with ISS stages 1 (56%), 2 (40%) and 3 (5%). 37/54 patients had received HDM followed by stem cell transplant as part of first-line treatment. The MTD was reached at dose level 3 when the maximum of 3 SAEs in 5 patients was observed. After establishment of the MTD, the phase 2 part of the trial was performed with B 1.6 mg/m2 once weekly for 3 weeks, L 20 mg days 1–21 and D 20 mg days 1–2, 8–9, 15–16, for 8 cycles of 28 days followed by L maintenance 10 mg days 1–21 of a 28 days cycle. The median number of cycles was 6 in the dose-escalation phase and 7 cycles in phase 2. 7/12 (58%) patients in the dose-escalation phase and 23/42 (55%) patients in phase 2 started lenalidomide maintenance. Reasons for premature discontinuation of the protocol treatment were toxicity (14%), progression (24%), no response (5%) or other (14%). Polyneuropathy grade 3–4 occurred in 19% with a median time to maximum PNP of 123 days. Hematological toxicity grade 3 and 4 was observed in 29 % of patients In the phase 2 part including 42 patients the ORR was 92 %, ≥VGPR 64% and CR/nCR 30%. Median time to response was 1.1 cycles. At a median follow-up of 13.6 months PFS at 18 months was 52% and OS 76%. Among predetermined risk factors ISS stage, prior HDM/ASCT and achieved response on protocol, depth of response was the only significant factor which was associated with PFS (p<0.001) and OS (p<0.001), Eight patients died from progressive MM (n=4) or other causes (n=4). One second primary malignancy was observed in dose level 3. Conclusions: Escalated VRD followed by Lenalidomide maintenance is effective and feasible in patients with first relapse MM. We will present an updated follow-up at ASH This trial was registered as Eudract nr 2007–002533–37. Unrestricted grants and study drug were provided by Janssen and Celgene. Disclosures: Sonneveld: Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Onyx: Honoraria, Research Funding.

A phase I dose escalation study of pemetrexed in patients with advanced head and neck squamous cell cancer (HNSCC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 6055-6055 ◽  
Author(s):  
P. H. Morrow ◽  
B. S. Glisson ◽  
L. E. Ginsberg ◽  
S. M. Lippman ◽  
M. S. Kies ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Cell Cancer ◽  
Maximum Tolerated Dose ◽  
Vitamin Supplementation ◽  
Dose Escalation Study ◽  
Grade 3 ◽  
Ecog Ps ◽  
Dose Levels ◽  
Neck Squamous Cell Cancer

6055 Background: Despite recent advances in therapy, patients (pts) with recurrent or metastatic HNSCC continue to demonstrate a poor median survival. In these pts, early trials with pemetrexed, a novel antimetabolite that acts upon several enzymes involved in pyrimidine and purine synthesis, have demonstrated promising efficacy and tolerability. Prior studies found that the administration of oral dexamethasone with pemetrexed reduced the incidence of skin rash. Later, vitamin supplementation (B12 and folic acid), given in addition to the dexamethasone, further diminished side effects. However, no trial has yet evaluated the appropriate steroid dose and its relation to the dosing of pemetrexed, in the setting of vitamin supplementation. We conducted a phase I trial to determine the maximum tolerated dose, toxicity, and preliminary efficacy of pemetrexed when given with different schedules of, or in the absence of, dexamethasone in pts with advanced HNSCC who had been treated with at least one or more chemotherapy regimens. Methods: Eligible pts had metastatic or recurrent HNSCC, prior treatment with one or more chemotherapy regimens, ECOG PS =2, and life expectancy >3 months. A conventional algorithm-based dose escalation design was applied, with three predefined dose levels (DL) of pemetrexed (500 mg/m2, 600 mg/m2, and 700 mg/m2) within each schedule of dexamethasone (none, 20 mg IV on day 1, and 4 mg orally bid for 3 days). Results: A total of 23 pts have been enrolled; 18 pts were evaluable. Median age was 57 years (range 47–82). Median ECOG PS was 1 (range 0–2), and 75% of pts were male. Number of prior chemotherapy regimens were as follows: 1 (40%), 2 (35%), 3 (15%), and 4 (10%). Preliminary data demonstrated only 2 treatment-related adverse events that were grade 3 or greater: anemia (DL1) and pneumonia (DL 1). In all, 13 pts have received pemetrexed with less than standard recommended dexamethasone dosing (none or IV), including 7 pts who received no dexamethasone. Of the 18 evaluable pts, 1 pt had a partial response and 2 pts had stable disease. Conclusions: This represents the first study that demonstrates that steroids may not be required as premedication with pemetrexed. Due to the limited toxicity observed, trial enrollment continues with dose escalation. [Table: see text]

Phase I dose escalation of ibrutinib and buparlisib in relapsed/refractory diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and follicular lymphoma (FL).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7544-7544 ◽  
Author(s):  
Connie Lee Batlevi ◽  
Paul A. Hamlin ◽  
Matthew J. Matasar ◽  
Steven M. Horwitz ◽  
John F. Gerecitano ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Serious Adverse Events ◽  
Pi3k Inhibitors ◽  
Grade 3 ◽  
Dose Reductions

7544 Background: In vitro studies of BTK and PI3K inhibitors demonstrate synergy in non-Hodgkin lymphoma (NHL). We embarked on a phase I/Ib investigator-initiated clinical trial evaluating the combination of ibrutinib (BTK inhibitor) and buparlisib (pan-PI3K inhibitor) in relapsed/refractory (R/R) NHL. The completed dose escalation is reported. Methods: Patients (pts) were eligible if they had R/R DLBCL, MCL, or FL with ECOG≤2 and adequate organ function. Ibrutinib and buparlisib were given daily by mouth on a 28-day cycle. Dose reductions were permitted after cycle 1. Tumor response was based on Lugano Classification however CR required both PET resolution and ≥ PR by CT. Results: As of Dec 16, 2016, 13 pts were enrolled and evaluated for toxicity (DLBCL 5, FL 2, MCL 6). Dose levels and DLT per table. Six pts discontinued treatment for disease progression (DLBCL 4, FL 2). Hematologic AE ≥ grade 3 are anemia (2), leukocytosis (2), and leukopenia (4). Relevant non-hematologic AEs of any grade ≥ 20% across all pts were fatigue (77%), diarrhea (62%), anorexia (54%), rash (46%), hyperbilirubinemia (46%), gastric reflux (46%), CMV reactivation (31%), mood change (31%), and hypertension (23%). Most common related grade 3/4 toxicity is rash (N = 3). No grade 5 toxicities noted. Serious adverse events (SAE) include: grade 2 pleural effusion and grade 2 nausea (N = 1), grade 1 fever with hospitalization (N = 1), grade 2 confusion and grade 4 hyponatremia (N = 1) were unrelated to therapy. Responses noted in 13 pts: MCL (N = 6: CR 4, PR 2), FL (N = 2: SD 2), DLBCL (N = 5: SD 1). One CR was a MCL pt with CR after 2 cycles on combination therapy and continues in remission on ibrutinib alone because of buparlisib toxicity. Conclusions: Combination of ibrutinib and buparlisib while generally well tolerated has predicted toxicities of both BTK and PI3K inhibitors. The recommended phase 2 dose is ibrutinib 560 mg and buparlisib 100 mg though dose reductions for tolerability may be needed for long term oral therapies. Promising efficacy is observed in MCL. Clinical trial information: NCT02756247. [Table: see text]

Sign in / Sign up

Export Citation Format

Share Document