A first-in-human phase I study of the oral p38 MAPK inhibitor LY2228820 dimesylate in patients with advanced cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3001-3001 ◽  
Author(s):  
Matthew P. Goetz ◽  
Anthony W. Tolcher ◽  
Paul Haluska ◽  
Kyriakos P. Papadopoulos ◽  
Charles Erlichman ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
P38 Mapk ◽  
Advanced Cancer ◽  
Phase I Study ◽  
Single Agent ◽  
Clinical Activity ◽  
Dependent Manner ◽  
Dose Levels ◽  
Dose Dependent

3001 Background: p38 MAPK regulates production of cytokines by the tumor microenvironment and its activation enables cancer cells to survive in the presence of oncogenic stress, radiation, chemotherapy, and targeted therapies. LY2228820 is a selective small-molecule inhibitor of p38 MAPK and preclinical studies demonstrate antitumor activity as a single agent and in combination with standard agents. We performed a phase I study to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of LY2228820 and to characterize its pharmacokinetics and pharmacodynamics. Methods: Dose escalation was performed in a 3+3 design. LY2228820 was taken orally every 12 hours on days 1-14 of a 28-day cycle. Results: 54 patients received either capsules at 8 dose levels (10, 20, 40, 65, 90, 120, 160, and 200mg) or tablets at 5 dose levels (160, 200, 300, 420, and 560mg). For both formulations, Cmax and AUC increased in a dose-dependent manner. LY2228820 inhibited p38 MAPK induced phosphorylation of MAPKAP-K2 in peripheral blood with dose-dependent maximum inhibition from 10 to 70% across the dose range 10-200mg. The most common drug-related adverse events included fatigue, nausea, rash, constipation, vomiting, and pruritus. 1 patient (200mg) had DLT of erythema multiforme (Gr3) and 2 patients (560mg) had DLT of ataxia (Gr3) and dizziness (Gr2), respectively. Although the MTD was 420mg, the frequency of Gr1/2 adverse events (mainly rash, dizziness, and tremor) and observation of clinical activity at lower dose levels led to a recommended dose of 300mg (mean AUC0-24 = 11.7ug-hr/ml at steady state). Early clinical activity has been observed in ovary, breast, and kidney cancers. One patient with metastatic clear cell carcinoma of the kidney refractory to sorafenib, sunitinib, and temsirolimus had confirmed near partial response (29% decrease) after 8 cycles and remains on therapy. 15 patients (28%) achieved best overall response of stable disease, which in 12 patients (22%) was prolonged (≥4 cycles). Conclusions: LY2228820 demonstrates acceptable pharmacokinetics, safety, and early clinical activity as a single agent in advanced cancer. A phase II study for patients with ovary cancer is planned.

Clinical activity and safety of the histone deacetylase inhibitor MGCD0103: Results of a phase I study in patients with leukemia or myelodysplastic syndromes (MDS)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6500-6500 ◽  
Author(s):  
G. Garcia-Manero ◽  
M. Minden ◽  
Z. Estrov ◽  
S. Verstovsek ◽  
W. M. Newsome ◽  
...  
Keyword(s):  
Phase I ◽  
Performance Status ◽  
Single Agent ◽  
Median Number ◽  
Myelogenous Leukemia ◽  
Clinical Activity ◽  
Tumour Suppressor Genes ◽  
Dependent Manner ◽  
Hdac Inhibition ◽  
Dose Dependent

6500 Background: MGCD0103 is a novel inhibitor of human histone deacetylases (HDACs), with selectivity for the cancer-associated isoforms of class I HDACs. Deacetylation of histones by HDACs is postulated to inactivate tumour suppressor genes leading to neoplastic transformation, and therefore inhibition of this enzyme may result in antineoplastic activity. Methods: To study the safety and activity of MGCD0103, we have developed a phase I open-label dose escalation study of MGCD0103 administered orally, three-times weekly in patients with leukemia or MDS, with the primary endpoints being the determination of the maximum tolerated dose (MTD) and the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of MGCD0103. Eligibility criteria included appropriate performance status and renal and hepatic functions. Patients with relapsed/refractory leukemia or MDS and older patients with untreated AML/MDS were eligible. Results: Twenty patients have been enrolled at four dose levels (20, 40, 80 and 60 mg/m2) so far. Their characteristics are: median age 60 years (range 33–76); the majority of patients so far treated have AML; median number of prior therapies is 1 (range 0–3). Most patients had complex cytogenetics. MGCD0103 has been well tolerated at doses below 80 mg/m2. The MTD has been reached, with 3 out of 4 patients at a dose of 80 mg/m2 developing grade 3 toxicity, mainly fatigue, nausea, vomiting or diarrhea. Grade 2 toxicities include anorexia, constipation, dehydration. The median number of courses is 1 (range 1 to 6). As of January 2006, 7 patients are on study. PK evaluations show dose-dependent exposure. Analysis of peripheral blood cell HDAC activity indicates that HDAC inhibition occurs in all patients in a dose-dependent manner. Two patients with multiple relapsed/refractory acute myelogenous leukemia, and one with MDS have achieved a complete marrow response (blasts less than 6%). Of importance, maximal HDAC inhibition was observed in those patients at the time of best response. Conclusions: Single-agent MGCD0103 has clinical activity and is well tolerated at doses below 80 mg/m2 orally three times a week in patients with advanced leukemia. No significant financial relationships to disclose.

A phase I study of AEE788, a multitargeted inhibitor of ErbB and VEGF receptor family tyrosine kinases, to determine safety, PK and PD in patients (pts) with advanced colorectal cancer (CRC) and liver metastases

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4065-4065 ◽  
Author(s):  
H. Q. Xiong ◽  
C. Takimoto ◽  
F. Rojo ◽  
D. Davis ◽  
J. Huang ◽  
...  
Keyword(s):  
Phase I ◽  
Liver Metastases ◽  
Phase I Study ◽  
Laser Scanning ◽  
Safety Data ◽  
Clinical Activity ◽  
Vegf Receptor ◽  
Dependent Manner ◽  
Dce Mri ◽  
Dose Dependent

4065 Background: AEE788 (AEE) is an oral inhibitor with potent activity against EGFR, ErbB2, and KDR. This phase I study was to assess the safety, PK, PD, and MTD/DLT of AEE in pts with CRC and liver metastases. Methods: AEE was given PO at 25, 50, 100, 250, 300 or 400 mg/day daily in 28-day cycles (C) to 3–6 pt cohorts. 24-hr PK was obtained on C1, days (D)1, 15 and 28. PK parameters of AEE and active metabolite, AQM674 (AQM) were computed by non-compartmental methods. PD markers were analyzed in skin (SK), and tumor (TU) biopsies pre- and post-treatment. Samples were evaluated by both IHC and Laser Scanning Cytometry (LSC). DCE-MRI was performed at baseline (BL), and on C1D2 and 28 and C2D28. Results: 22 pts were treated at doses of 25 (n=4), 50 (n=3), 100 (n=4), 250 (n=1), 300 (n=4), and 400 mg (n=6). No DLT was reported. The most common AE (> 15%): fatigue (55%), vomiting (46%), diarrhea (41%), nausea (36%), dyspnoea (23%), constipation (18%) pyrexia (18%) and rash (18%). 2 pts had reversible gr 3/4 LFTs. Serum concentration of AEE and AQM increases with dose and dose duration. 7 pts had stable disease at the end of C2. Median time on treatment was 56 days (range 7–168). In SK, at doses =100 mg, pEGFR, pMAPK and Ki67 were inhibited by an average of 51, 54 and 41%, respectively by IHC. In endothelial cell (EC) pKDR/KDR was significantly inhibited (4-fold) in the wound-induced SK in a dose-dependent manner by LSC. In TU, inhibition of pEGFR, pMAPK and Ki67 at 400 mg was 100%, 90% and 39%, respectively by IHC. EC pKDR decreased with dose, however, trend was not significant. 1 out 15 pts who had BL and end of C1 DCE-MRI had > 40% Ktrans reduction. Conclusions: A dose dependent inhibition of pKDR, pEGFR, and pMAPK in skin and tumor was observed. However, no significant effects were observed on Ki67 and apoptosis in TU. No dose dependent reduction in Ktrans from DCE-MRI was observed. These findings were consistent with the lack of clinical activity of AEE up to 400 mg in this patient population. The study has been discontinued without reaching DLT due to safety data from other phase I studies and in favor of different dosing schedules. No significant financial relationships to disclose.

BT062, An Antibody-Drug Conjugate Directed Against CD138, Shows Clinical Activity In a Phase I Study In Patients with Relapsed or Relapsed/Refractory Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3060-3060 ◽  
Author(s):  
Sundar Jagannath ◽  
Asher A. Chanan-Khan ◽  
Leonard T Heffner ◽  
David Avigan ◽  
Robert J Lutz ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase I Study ◽  
Clinical Activity ◽  
Antibody Drug Conjugate ◽  
Advisory Committees ◽  
Elimination Phase ◽  
Dose Levels

Abstract Abstract 3060 Background: CD138 represents one of the most reliable target antigens for identification of multiple myeloma (MM) cells and has been reported to be a highly sensitive and specific diagnostic marker of MM. BT062 (Biotest AG Dreieich, Germany) is an antibody-drug conjugate, comprised of the anti-CD138 chimerized MAb (nBT062) and the cytotoxic agent DM4. Once bound to CD138 on a target cell, the conjugate is internalized and releases DM4, leading to targeted cell death. Preclinical investigations demonstrated strong in vitro and in vivo anti-MM activity of BT062, providing the rationale for the conduct of clinical trials (Ikeda et al., 2009). Objectives: To determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), pharmacokinetics (PK) and anti-MM activity of increasing doses of BT062 on a repeated single dose schedule once every three weeks in patients with relapsed and/or refractory MM. Toxicities were assessed by CTCAE v3 and clinical response was assessed according to the international working group criteria. Methods: This is a prospective, open label, dose-escalation multicenter study. Patients aged ≥ 18 years with relapsed or relapsed/refractory MM who have failed previous treatments including an immunomodulatory agent and a proteasome inhibitor were eligible to participate. Patients with clinical response (or no evidence of progressive disease) and without unacceptable toxicities were eligible for further treatment cycles. Patients were enrolled in cohorts of 3 at each dose level, with DLT in the first cycle triggering cohort expansion. Results: A total of 32 patients have been treated with BT062, receiving one of 7 dose levels ranging from 10 mg/m2 to 200 mg/m2. Maximum administered dose has been defined at 200 mg/m2, with mucositis as the dose limiting toxicity (CTC grade III in 2 of the 3 patients in this cohort). Therefore, the MTD was defined at 160 mg/m2. Thirteen of 32 patients have been treated in an expanded MTD-cohort. No CTC grade 4 toxicity has been reported. The most frequently reported adverse events to date cover primarily events expected for the underlying disease and patient group. Most of the reported adverse events are CTC grade I to II. Nevertheless, a few adverse events have also been observed involving skin and/or mucosa (tissues of epithelial origin with CD138 expressing cells), as well as the eye. Severe events involving skin and/or mucosa (e.g. mucositis, hand/foot syndrome) have only been observed at the dose levels 160 mg/m2 or higher. Adverse events involving the eye (e.g. blurred vision, dry eye) have been reported in only 3 patients overall at the dose levels 160 mg/m2 or higher, all CTC grade I to II. At dose levels up to 120 mg/m2, preliminary PK results indicate an unusual rapid clearance from plasma in the early elimination phase, followed by a generally normal terminal elimination phase. A more typical clearance profile was observed for all patients at the 160 mg/m2 and 200 mg/m2 dose. To date, one patient showed a decrease in urine M-Protein by >50% after 8 repeated low doses of 20 mg/m2 each. At a high dose level of 160 mg/m2, another patient showed a >50% decrease of serum FLC after two doses of BT062. In total, stabilization of disease was noted in 13 patients. Patients with stable disease received a median of 5 cycles of therapy (range of 3–10). Most patients came off study due to disease progression. Conclusion: Preliminary data from this phase I study demonstrate an acceptable toxicity profile of BT062. Even in this phase I patient population, evidence of clinical activity was observed. Based on the favourable safety profile, the pharmacokinetic data and early signs of clinical activity, a Phase I/II study in MM is initiated to further evaluate the safety and anti-MM efficacy of BT062 in a more frequent dosing regimen. Updated results on safety, PK and efficacy of BT062 will be presented. Disclosures: Jagannath: Celgene: Honoraria; Millenium/Takeda Pharma: Honoraria; J&J Family: Honoraria; Onyx: Honoraria; Merck: Honoraria. Heffner:Millennium: Research Funding. Avigan:Genzyme: Consultancy, Research Funding; Celgene: Research Funding; Curetec: Research Funding. Lutz:ImmunoGen, Inc.: Employment. Uherek:Biotest AG: Employment. Osterroth:Biotest AG: Employment. Ruehle:Biotest AG: Employment. Haeder:Biotest AG: Employment. Niemann:Biotest AG: Employment. Wartenberg-Demand:Biotest AG: Employment. Munshi:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Anderson:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Merck: Consultancy; Bristol Myers Squibb: Consultancy; Acetylon: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Phase I Study of Single-Agent Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Patients with Advanced Cancer

2018 ◽  
Vol 24 (8) ◽  
pp. 1816-1823 ◽  
Author(s):  
Neil H. Segal ◽  
Aiwu R. He ◽  
Toshihiko Doi ◽  
Ronald Levy ◽  
Shailender Bhatia ◽  
...  
Keyword(s):  
Phase I ◽  
Advanced Cancer ◽  
Phase I Study ◽  
Single Agent

Phase I/II study of a novel oral isotype-selective histone deacetylase (HDAC) inhibitor MGCD0103 in combination with azacitidine in patients (pts) with high-risk myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7062-7062 ◽  
Author(s):  
G. Garcia-Manero ◽  
A. S. Yang ◽  
V. Klimek ◽  
S. Luger ◽  
W. M. Newsome ◽  
...  
Keyword(s):  
Phase I ◽  
Hdac Inhibitor ◽  
Dna Methyltransferase ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Myelogenous Leukemia ◽  
Clinical Activity ◽  
Relevant Dose ◽  
Aberrant Dna Methylation ◽  
Dose Levels

7062 Background: Aberrant DNA methylation and histone acetylation are common in leukemia. The HDAC inhibitor MGCD0103 (0103) and the DNA methyltransferase inhibitor azacitidine (aza); which is approved for all FAB subtypes of MDS, synergize preclinically and both have single-agent activity in MDS and AML. Based on these data, we developed a Phase I/II study of combination aza + 0103 in pts with AML and MDS. Phase I data is presented. Methods: Pts with advanced MDS (=10% marrow blasts), relapsed/refractory or untreated elderly patients with AML were treated with aza 75 mg/m2 SC daily for 7d of each 28-day cycle and 0103 110mg 3x/week starting on day 5. The primary endpoint was determination of the maximum tolerated dose (MTD) of the combination. The phase I portion followed “3+3” model; only 0103 was escalated. Results: Dose levels of 0103 explored were 35, 60, 90, 110 and 135 mg. 24 pts (those having received =1 dose of MGCD0103) have been evaluated; AML=22, MDS=2. Median age 67 (40–85), total cycles=56 (mean=2.3, range=1–11). Dose limiting toxicities observed: vomiting (1/8 pts at 90 mg), nausea & anorexia (2/3 pts at 135 mg), and anorexia (1/6 pts at 110 mg). The MTD of 0103 in the combination was determined to be110 mg. PK characteristics of neither drug was altered by co-administration. 7/9 pts had significant reduction of whole cell HDAC activity during treatment with the combination. Antileukemia activity was documented in 7 pts; 6 of which were among 14 at the 2 most relevant dose levels (90 & 110 mg): 3 CR, 1 PR, and 3 CR without platelet or neutrophil recovery (required for per- protocol response). Of these 7, 4 are ongoing and 3 have been discontinued: 1 to transplant and 2 for SAEs. Conclusions: The Phase I portion of the trial demonstrates that the 0103+aza combination is safe in pts with advanced AML/MDS, and has encouraging biologic & clinical activity. Phase II portion of the study is ongoing at MTD. Molecular studies are ongoing. No significant financial relationships to disclose.

A phase I study of bortezomib in combination with 5FU/LV plus oxaliplatin in patients (pts) with advanced colorectal cancer (CRC): EORTC 16029

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4090-4090 ◽  
Author(s):  
D. A. Lacombe ◽  
F. Caponigro ◽  
A. Anthoney ◽  
J. Bauer ◽  
A. Govaerts ◽  
...  
Keyword(s):  
Phase I ◽  
Stable Disease ◽  
Phase I Study ◽  
Sensory Neuropathy ◽  
Reversible Inhibitor ◽  
Disease Rate ◽  
Clinical Activity ◽  
Starting Dose ◽  
Proteasome Pathway ◽  
Dose Levels

4090 Background: Bortezomib is a potent and reversible inhibitor of the ubiquitin-mediated proteasome pathway, whose inhibition results in the stabilization of p53, p21Cip1, p27Kip1, Bax, in cell-cycle dysregulation and, finally, apoptosis. A phase I study of the combination of 5FU/LV and bortezomib has shown a significant stable disease rate in advanced CRC (Iqbal, ASCO 2004). Methods: In this phase I study bortezomib was given as an IV push over 3 to 5 seconds on days 1, 8 and 15 in combination with standard FOLFOX-4 every 28 days in chemo-naïve pts with advanced CRC. Bortezomib starting dose level was 1.3 mg/m2. A 3+3 study design was utilized at predefined dose levels (DL). Dose-limiting-toxicity (DLT) was assessed during cycle 1. Exploratory pharmacogenetics research was conducted. Results: 15 pts were treated and 46 cycles given. At DL2 (1.6 mg/m2), 2/4 pts experienced a DLT: G3 febrile neutropenia causing treatment delay and bortezomib dose reduction in 1pt and one bortezomib dose skipped due to persistent G2 peripheral neuropathy and myalgia in 1pt. At DL1 (1.3 mg/m2), 2/6 pts had a DLT. Both pts experienced a G3 neutropenia on day 15, which prevented treatment from being given as scheduled. DL-1 (1 mg/m2) was therefore investigated and no DLT was observed among 5 pts. The most frequently reported toxicities in cycle 1 were γGT (64%), nausea, fatigue and sensory neuropathy (53%), pain (33%), diarrhea and fever (27%), vomiting (20%), anorexia, dyspnea and mucositis (13%) and neutropenia 29% (G2,3). 12 pts are currently evaluable for response; 6 had a partial response, 3 stable disease and 3 disease progression. Conclusion: The toxicity profile of this combination is predictable and early evidence of clinical activity has been observed. The recommended bortezomib dose for further investigation within this regimen is 1 mg/m2. No significant financial relationships to disclose.

Thalidomide (T) in Combination with Fludarabine (F) as Initial Therapy for Patients (pts) with Treatment Naïve Chronic Lymphocytic Leukemia (CLL): Results of a Phase I Trial.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3476-3476
Author(s):  
Asher Alban Chanan-Khan ◽  
Kena Miller ◽  
Alexandra Koryzna ◽  
Kenichi Takeshita ◽  
Philip McCarthy ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Standard Dose ◽  
Initial Therapy ◽  
Lymphocytic Leukemia ◽  
Common Side Effect ◽  
Clinical Activity ◽  
Immunostimulatory Activity ◽  
Incurable Disease ◽  
Dose Levels

Abstract CLL is an incurable disease. Standard treatment with F results in an ORR of 63% (CR 20%). Improved RR are noted when F is combined with biologic agents such as rituximab. All pts eventually relapse with limited salvage options. TNF-a is an important cytokine in the pathogenesis of CLL. T is an immunomodulatory drug with anti- TNF-a, anti-VEGF and immunostimulatory activity. We have completed a phase I study combining T with F as an immunochemotherapeutic approach to enhance anti-CLL activity of F. Treatment-naïve pts requiring therapy for CLL were eligible for this study. T was started at D1 and continued for 6 months stepwise in 3 cohorts of T (100,200,300 mg). Standard dose F (25mg/m2 x 5 D every 4 wks) was given for 4–6 cycles starting on D7. Antitumor activity of T alone was assessed at D7 prior to the first F dose. Low-dose coumadin (1 or 2 mg po qd) was used for prophylaxis against venous thromboembolism (VTE). Thirteen pts (9M, 4F; median age 65,range 38–74 yrs) have been enrolled on 3 dose levels (cohort #1 n =6, #2 n=3, #3 n=4). All pts are available for toxicity analysis. Pts were considered evaluable for response if they completed the intended 6 months of T. 3 pts were removed from study for toxicity (2VTE, 1 in the 1st week of therapy prior to F infusion, 2nd during the 4th cycle, 1 Hep C reactivation presumably secondary to F), without evidence of disease progression. 9 pts completed 6 months of therapy and are available for response (5CR and 4PR, ORR of 100%) median follow-up of 12+ (range 6–18+) months. Response to T alone, assessed on D7 of cycle 1, was noted at all dose levels, and no dose-limiting toxicity was noted. Flare reaction (tender swelling of lymph nodes) was noted in 5/13 pts (38%) and was the most common side effect. Rash, fatigue and constipation were noted in 30%, 23% and 15% of the pts, respectively. Of the 60 cycles given on this study, 9 (15%) and 3 (5%) episodes of Grade III and IV non-hematologic toxicities were noted, respectively. In this phase I study, the combination of T with F was well tolerated with improved ORR over F. T alone appears to be active in CLL with clinical activity noted as early as D 7 at all dose levels studied. The combination does not appear to increase the incidence of VTE compared to T alone. Ongoing phase II portion of this study will further establish the potential role of FT in CLL.

Safety and Efficacy Results from a Phase I Trial of Single-Agent Lumiliximab (Anti-CD23 Antibody) for Chronic Lymphocytic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2503-2503 ◽  
Author(s):  
John C. Byrd ◽  
Susan O’Brien ◽  
Ian Flinn ◽  
Thomas J. Kipps ◽  
Mark A. Weiss ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
Phase I ◽  
Performance Status ◽  
Single Agent ◽  
Patient Characteristics ◽  
Outpatient Setting ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Treatment Regimens

Abstract The CD23 antigen is expressed at high density on the cell surface of certain B-cell malignancies, including chronic lymphocytic leukemia (CLL). Lumiliximab (L-mab), a macaque-human chimeric anti-CD23 monoclonal antibody, has been reported to have antitumor activity against CLL in preclinical studies. In this Phase I multicenter study, the safety, efficacy, and pharmacokinetics of single-agent L-mab were evaluated in 46 patients with relapsed or refractory CLL. Therapy consisted of intravenous L-mab given as 6 regimens: (1) 125 mg/m2/wk for 4 weeks; (2) 250 mg/m2/wk for 4 weeks; (3) 375 mg/m2/wk for 4 weeks; (4) 500 mg/m2/wk for 4 weeks; (5) 500 mg/m2 for 3 doses during Week 1, then 500 mg/m2/wk during Weeks 2 to 4; and (6) 500 mg/m2 three times a week for 4 weeks. Patient characteristics were as follows: median age of 62 years (range 47 to 80 years), 93% Caucasian, 72% male, 54% fludarabine-refractory, 48% Rai stage III/IV, and 78% WHO Performance Status 1. At study entry, patients had progressive CLL after 1 to 13 prior treatment regimens (median = 4 prior regimens). Antibody infusions, administered over 2 hours in an outpatient setting, were well tolerated. Study-related adverse events (probable, possible, or unknown relationship to study treatment) were reported in 40 of 46 patients (87%). The majority of events were Grade 1 or 2; the most common were headache, constipation, nausea, and cough. Grade 3 or 4 study-related adverse events were reported in 7 of 46 patients (15%) and included neutropenia and dyspnea. Evidence of clinical activity consisted of reductions in absolute lymphocyte counts (ALC) and lymphadenopathy. Decreases in ALC were observed in 42 of 46 (91%) patients, and decreases ≥ 50% were observed in 11 of 40 (28%) patients enrolled at 375 mg/m2/week or higher. Of 37 patients evaluated for change in lymphadenopathy, reductions were observed in 22 (59%). Flow cytometry revealed that L-mab saturated CD23 sites on CLL cells at doses above 375 mg/m2/week without down regulating CD23 expression. These results suggest that single-agent L-mab can be administered safely with evidence of clinical activity in patients with heavily pretreated CLL. Ongoing clinical studies are assessing the potential of L-mab in combination with rituximab and fludarabine-based chemotherapy.

Clofarabine Combinations in Acute Myeloid Leukemia (AML) Salvage: A Dose-Finding Phase I Study of Clofarabine Plus Idarubicin and Clofarabine/Idarubicin Plus Cytarabine (ara-C).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2803-2803
Author(s):  
Stefan Faderl ◽  
Alessandra Ferrajoli ◽  
William Wierda ◽  
Farhad Ravandi ◽  
Zeev Estrov ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Single Agent ◽  
Response Rates ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Unrelated Donor ◽  
Acute Leukemias ◽  
First Relapse ◽  
Dose Levels

Abstract Clofarabine is a second-generation nucleoside analog with single agent activity in acute leukemias. To try and improve efficacy, various combination trials are being conducted. In studies of clofarabine plus ara-C we reported overall response rates of 41% (CR 24%) in AML salvage and 60% (CR 52%) in untreated elderly AML with acceptable toxicity profile. To explore additional clofarabine combinations in AML we conducted a phase I study of clofarabine (C) with idarubicin (I) [CI] alone and with ara-C (A) [CIA] in pts with relapsed AML and high-grade MDS. Dose-limiting toxicities (DLT) were defined as ≥ grade 3 drug-related toxicities. Maximum tolerated dose (MTD) was determined by “3+3” method. Thirty-three patients (18 on CI and 15 on CIA) have been treated and are evaluable. Of 18 pts on CI, 6 were primary refractory and 12 in first relapse (median first remission duration [CRD1] 2 mos. [range 0–9]. Eleven pts had abnormal cytogenetics. Fourteen pts received prior ara-C-based regimens, 2 relapsed from allogeneic transplant (SCT). Median age: 57 yrs (range 24–71). Four dose levels have been explored. When C was given at 22.5mg/m2 i.v. daily x 5d and I at 12mg/m2 i.v. daily x 3d, 2 ≥ gr. 3 toxicities (diarrhea, rash, ↑ bili) occurred necessitating dose de-escalation. Subsequent levels included C at 15mg/m2 x 5d/I at 8mg/m2 x 3d (6 pts, 1 ≥ gr.3 toxicity [↑ bili]), C at 18 mg/m2 x 5d, I at 10mg/m2 x 3 d (3 pts, no DLT), and C at 22.5mg/m2 x 5d, I at 10mg/m2 x 3d (3 pts, no DLT). Three (17%) responses (2 CRp, 1 CR) occurred. Of 15 pts on CIA, 4 were primary refractory and 11 in first relapse. Median CRD1 was 9 mos (0–24). Eight pts had an abnormal karyotype. Seven pts received prior ara-C-based regimens and 2 failed unrelated donor SCT. Median age: 58 yrs (23–78). Three dose levels were evaluated. At C 22.5mg/m2 i.v. daily x 5d, I 8mg/m2 i.v. daily x 3d, A 1g/m2 i.v. daily x 5d, 2 of 3 pts developed ≥ gr.3 toxicities (↑ bili, diarrhea) necessitating dose de-escalation. Subsequent levels included C at 15mg/m2 x 5d, I at 6mg/m2 x 3d, A at 0.75g/m2 x 5d (6 pts, 1 with ≥ gr. 3 rash, ↑ bili), and C at 22.5mg/m2 x 5d, I at 6mg/m2 x 3d, and A at 0.75g/m2 x 5d (6 pts, 1 with ≥ gr. 3 ↑ bili). Nine (60%) responses (8 CR, 1 CRp) occurred. Further dose escalation of clofarabine is planned in both trials. The preliminary results indicate feasibility of the combinations. The higher response rates with CIA need to be evaluated in view of different pt. characteristics between the two trials.

SGN-40 (Anti-huCD40 mAb) Monotherapy Induces Durable Objective Responses in Patients with Relapsed Aggressive Non-Hodgkin’s Lymphoma: Evidence of Antitumor Activity from a Phase I Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 695-695 ◽  
Author(s):  
Ranjana Advani ◽  
Andres Forero-Torres ◽  
Richard R. Furman ◽  
Joseph D. Rosenblatt ◽  
Anas Younes ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Adverse Events ◽  
Phase I ◽  
B Cell ◽  
Phase I Study ◽  
Maximum Dose ◽  
Single Agent ◽  
Objective Response ◽  
Pharmacokinetic Parameters ◽  
Hepatic Transaminases

Abstract CD40 is a member of the TNF receptor family and is widely expressed on B-cell malignancies. SGN-40 is a humanized antibody against CD40 with effector cell function and partial agonistic activity. Based on potent in vitro and in vivo preclinical activity, a multi-institutional, multi-dose phase I study was conducted to test the safety, pharmacokinetic properties, immunogenicity, and antitumor activity of intravenous SGN-40 in patients with relapsed NHL. Patients with multiple histologic subtypes of NHL were enrolled on this study, including diffuse large B-cell (DLBCL; 14), follicular (FCL; 9), mantle cell (MCL; 9), marginal zone (MZL; 2) and small lymphocytic (SLL; 1). After dose-dependent inflammatory symptoms were identified following the first infusion of SGN-40 in a separate phase I study (i.e. cytokine release syndrome, including headache, fever, muscle aches), this study was modified such that patients were treated with a dose-loading schedule: 1 mg/kg of SGN-40 on day 1 and day 4 and subsequent intra-patient dose-escalation during weeks 2–5 to a maximum dose of 3, 4, 6, or 8 mg/kg over four cohorts. Subsequently, a rapid dose-loading schedule was tested in one cohort (40% increase in total SGN-40 administered during cycle 1). Responding patients or those with stable disease were eligible for a second cycle, consisting of four consecutive weekly infusions at the cohort-specific maximum dose of SGN-40. Most adverse events were grade 1 or 2 and included fatigue (31%), headache (26%), chills (17%), pyrexia (17%), elevated hepatic transaminases (11%), and hypotension (11%). Transient drug-related grade 3 adverse events included conjunctivitis and unilateral loss of visual acuity, anemia, and elevated hepatic transaminases, each in a single patient. There was no difference in the incidence or severity of adverse events at higher doses of SGN-40 nor was there a difference in the safety profiles of the gradual vs. rapid dose-loading schedules. Ten of 35 enrolled patients received a second cycle of treatment without any evidence of cumulative toxicity. No immune responses against SGN-40 have been detected among 16 NHL patients tested to date. Preliminary pharmacokinetic parameters are similar to those seen in preclinical toxicity studies. Durable objective responses have been observed in heavily pre-treated patients. Eight patients with DLBCL completed cycle 1 and received a maximum dose of at least 3 mg/kg SGN-40 with an objective response rate of 37.5% (i.e. 1 CR and 2 PR) and 2 SD. Additional objective responses were seen in one patient with MCL (CR) and one patient with MZL (PR). The median duration of response for these 5 patients has not yet been reached (range 8–37 weeks). Analyses are ongoing to evaluate the role of CD40 expression levels and the relationship of FcγR polymorphisms to response. In conclusion, SGN-40 has favorable safety data and encouraging antitumor activity. A phase II study of single-agent SGN-40 in patients with relapsed DLBCL is planned.

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