scholarly journals A phase 1 trial of the Fc-engineered CD19 antibody XmAb5574 (MOR00208) demonstrates safety and preliminary efficacy in relapsed CLL

Blood ◽  
2014 ◽  
Vol 124 (24) ◽  
pp. 3553-3560 ◽  
Author(s):  
Jennifer A. Woyach ◽  
Farrukh Awan ◽  
Ian W. Flinn ◽  
Jesus G. Berdeja ◽  
Elizabeth Wiley ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase 1 ◽  
Single Agent ◽  
Phase 1 Trial ◽  
Key Points

Key Points XmAb5574 is an Fc-engineered CD19 monoclonal antibody that is well tolerated as a single agent in patients with relapsed or refractory CLL. XmAb5574 has preliminary efficacy as a single agent in CLL and is of interest for further study in this disease.

scholarly journals A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33-positive acute myeloid leukemia

Blood ◽  
2018 ◽  
Vol 131 (4) ◽  
pp. 387-396 ◽  
Author(s):  
Eytan M. Stein ◽  
Roland B. Walter ◽  
Harry P. Erba ◽  
Amir T. Fathi ◽  
Anjali S. Advani ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Myeloid Leukemia ◽  
Phase 1 ◽  
Single Agent ◽  
Antibody Drug Conjugate ◽  
Phase 1 Trial ◽  
Nonhematologic Toxicity ◽  
Key Points ◽  
Acute Myeloid ◽  
Antibody Drug

Key Points Vadastuximab talirine, a novel antibody-drug conjugate, consists of an anti-CD33 monoclonal antibody conjugated to pyrrolobenzodiazepine dimers. In a phase 1 trial, vadastuximab talirine demonstrated single-agent activity and minimal nonhematologic toxicity in patients with AML.

scholarly journals Multicenter phase 1 trial of intraventricular immunochemotherapy in recurrent CNS lymphoma

Blood ◽  
2013 ◽  
Vol 121 (5) ◽  
pp. 745-751 ◽  
Author(s):  
James L. Rubenstein ◽  
Jing Li ◽  
Lingjing Chen ◽  
Ranjana Advani ◽  
Jan Drappatz ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Phase 1 ◽  
Cns Lymphoma ◽  
Phase 1 Trial ◽  
Multicenter Phase ◽  
Key Points

Key Points Phase I study showed that intraventricular rituximab plus methotrexate is feasible and active in the treatment of refractory CNS lymphoma.

scholarly journals First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation

Blood ◽  
2018 ◽  
Vol 131 (23) ◽  
pp. 2515-2527 ◽  
Author(s):  
Rizwan Romee ◽  
Sarah Cooley ◽  
Melissa M. Berrien-Elliott ◽  
Peter Westervelt ◽  
Michael R. Verneris ◽  
...  
Keyword(s):  
T Cells ◽  
Clinical Study ◽  
Cell Expansion ◽  
Phase 1 ◽  
Single Agent ◽  
Cd8 T Cell ◽  
Key Points ◽  
Clinical Responses ◽  
Human Use

Key Points Single-agent IL-15/IL-15Rα-Fc (ALT-803) therapy was well tolerated and resulted in clinical responses in patients who relapsed post-HCT. First-in-human use of ALT-803 promoted NK and CD8+ T-cell expansion and activation in vivo without stimulating regulatory T cells.

Survival of patients considered for participation to contemporary dose-seeking phase trial: Matter of tumour burden, nature of treatment or of dose-levels?

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2549-2549
Author(s):  
Juliette Bouchet ◽  
Nicolas Isambert ◽  
Philippe Alexandre Cassier ◽  
Carlos Alberto Gomez-Roca ◽  
Stephanie Clisant ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factor ◽  
Phase I ◽  
Dose Level ◽  
Cox Model ◽  
Phase 1 ◽  
Single Agent ◽  
Cytotoxic Agents ◽  
Phase 1 Trial ◽  
Dose Levels

2549 Background: We have analyzed the survival of pts considered for participation to contemporary phase 1 trial. Methods: All consecutive pts having signed the PIS/IC have been analyzed. OS have been measured using Kalan-Meier method. RMS had been calculated, RMS (0 to 3) is sum of the following prognostic factors: LDH>ULN, met. sites>2 and albumin <35 g/L. Comparisons have been done with Log-rank tests and Cox model. Results: OS of the entire cohort was 448 days. 73.4% of pts having been enrolled. Among not enrolled pts, 74.1% of pts received another treatment. The OS was 497, 247 and 110 days, in pts enrolled in phase I trial, in pts not enrolled but receiving another treatment and in non-treated pts (p=0.001). After adjustment to RMS and with pts not enrolled but receiving other treatment as reference, the HR was 0.47 (95-CI:0.34-0.66; p=0.0001) in pts enrolled in phase 1 compared and 3.54 (1.92-6.52; p=0.0001) in non-treated pts. We have then more specifically analyzed the pts enrolled in single-agent dose-escalating phase I. The OS was 894, 272 and 395 days in pts receiving the 2 first dose-levels, in those receiving intermediate dose-levels and those receiving the phase 2-recommended dose, respectively (p=0.001). The OS was 328 in pts receiving molecular targeted agent and 539 in those receiving cytotoxic agents (p=0.004). In a multivariate analysis, the nature of investigational agent and the dose-level were not associated with better outcome. The sole prognostic factor for OS in multivariate analysis was the RMS (0+1 vs 2+3: HR=3.80 [1.76-8.20], p=0.01). Conclusions: Inclusion in phase 1 trial was associated with better outcome in both crude analysis and after adjustment to RMS. Among enrolled pts, in multivariate analysis RMS reflecting the tumor burden was the sole prognostic factor, the nature of the drug and the dose-level were not associated with the outcome.

A phase 1b study of the anti-PD-1 monoclonal antibody BGB-A317 (A317) in combination with the PARP inhibitor BGB-290 (290) in advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3013-3013 ◽  
Author(s):  
Michael Friedlander ◽  
Tarek Meniawy ◽  
Ben Markman ◽  
Linda R. Mileshkin ◽  
Paul R. Harnett ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Monoclonal Antibody ◽  
Solid Tumors ◽  
Phase 1 ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Advanced Solid Tumors ◽  
Phase 1 Study ◽  
Multiple Tumor ◽  
Study Results

3013 Background: The release of tumor-associated antigens may enhance the response to immunotherapy. BGB-A317, a humanized IgG4 variant monoclonal antibody engineered to have no Fc gamma receptor binding, targets the programmed cell death-1 (PD-1) receptor. It is being developed in solid and hematologic malignancies at a dose of 200 mg IV Q3W. BGB-290, a potent inhibitor of PARP 1/2, is hypothesized to promote neoantigen release that will potentially increase the efficacy of BGB-A317. A phase 1 study identified 60mg BID as the recommended Phase 2 dose (RP2D) for BGB-290. This study consists of initial dose escalation to determine the maximum-tolerated dose (MTD), safety, PK profile, and preliminary anti-tumor activity of the combination, followed by expansion into ovarian, breast, prostate, gastric, bladder, pancreatic and small cell lung cancers. Methods: Cohorts of 6 -12 pts with advanced solid tumors were treated in each of 5 planned dose levels (DLs). In DLs 1-3, BGB-290 doses ranged between 20-60mg PO BID with BGB-A317 2mg/kg IV Q3W. In DLs 4 - 5, BGB-290 doses were 40 or 60 mg BID; A317 was given at 200 mg IV Q3W based on PK data from a single agent Phase 1 study. Results: As of 16 Jan 2017, 38 pts [median age 59 years (34-75)] were treated in DLs 1-4; enrollment to DL5 is ongoing. One DLT of persistent Gr 2 nausea was reported in DL 4. The most common adverse event (AE) considered related to both study drugs was fatigue (10.5%). Immune-related AEs were Gr 3 hypophysitis (n = 1), Gr 3 or 4 autoimmune hepatitis(n = 2), and Gr 2 elevated AST/ALT (n = 1). Decreases in tumor burden have been observed in 16 pts; 7 achieved a PR (5 with ovarian and one each with uterine and pancreatic cancer) and one CR was observed in ovarian cancer. Six pts had SD for > 6 months including 2 pts with pancreatic cancer who received BGB-A317+BGB-290 for 189 and 281 days. Plasma/serum exposure of BGB-290 and BGB-A317 were consistent with those in single-agent trials. Conclusions: BGB290 and BGB-A317 can be combined. Dose expansion in multiple tumor types is planned to commence in 2017 once the RP2D is determined. Clinical trial information: NCT02660034.

A phase 1b study of the anti-PD-1 monoclonal antibody BGB-A317 (A317) in combination with the PARP inhibitor BGB-290 (290) in advanced solid tumors.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 48-48 ◽  
Author(s):  
Michael Friedlander ◽  
Tarek Meniawy ◽  
Ben Markman ◽  
Linda R. Mileshkin ◽  
Paul Harnett ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Autoimmune Hepatitis ◽  
Solid Tumors ◽  
Phase 1 ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Phase 1 Study ◽  
Study Results

48 Background: The release of tumor-associated antigens may enhance the response to immunotherapy. BGB-A317, a humanized IgG4 variant monoclonal antibody engineered to have no Fc gamma receptor binding, targets the programmed cell death-1 (PD-1) receptor. It is being developed in solid and hematologic malignancies at a dose of 200 mg IV Q3W. BGB-290, a potent inhibitor of PARP 1/2, is hypothesized to promote neoantigen release that may potentially increase the efficacy of BGB-A317. A phase 1 study identified 60 mg BID as the recommended Phase 2 dose (RP2D) for BGB-290. This study consists of initial dose escalation to determine the maximum-tolerated dose (MTD), safety, pharmacokinetic (PK) profile, and preliminary antitumor activity of the combination, followed by expansion into ovarian, breast, prostate, gastric, bladder, pancreatic and small cell lung cancers. Methods: Cohorts of 6–12 patients with advanced solid tumors were treated in each of 5 planned dose levels (DLs). In DLs 1–3, BGB-290 doses ranged between 20–60 mg PO BID with BGB-A317 2 mg/kg IV Q3W. In DLs 4–5, BGB-290 doses were 40 or 60 mg BID; A317 was given at 200 mg IV Q3W based on PK data from a single agent Phase 1 study. Results: As of 31 March 2017, 43 patients [median age 63 years (34–75)] were treated in DLs 1–5. Three patients experienced four dose-limiting toxicities: grade 2 nausea (DL4), grade 2 nausea and grade 2 vomiting (DL5), and grade 4 autoimmune hepatitis (DL5). MTD was identified as BGB-A317 200 mg IV Q3W + BGB-290 40 mg PO BID. The most common adverse event (AE) considered related to both study drugs was fatigue. Immune-related AEs of Grade ≥3 were elevated alanine aminotransferase/aspartate aminotransferase (n = 3), autoimmune hepatitis (n = 3), and hepatitis (n = 1). Complete or partial response was observed in 11 patients, 4 of whom had confirmed PR or CR. Plasma/serum exposure of BGB-290 and BGB-A317 were consistent with those in single-agent trials. Conclusions: The combination of BGB-A317 and BGB-290 was generally well tolerated in patients with advanced solid tumors. These results support the continuation of this trial with enrollment into the disease-specific cohorts. Clinical trial information: NCT02660034.

scholarly journals A phase 1 study evaluating the safety and tolerability of otlertuzumab, an anti-CD37 mono-specific ADAPTIR therapeutic protein in chronic lymphocytic leukemia

Blood ◽  
2014 ◽  
Vol 123 (9) ◽  
pp. 1302-1308 ◽  
Author(s):  
John C. Byrd ◽  
John M. Pagel ◽  
Farrukh T. Awan ◽  
Andres Forero ◽  
Ian W. Flinn ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Safety Profile ◽  
Phase 1 ◽  
Single Agent ◽  
Therapeutic Protein ◽  
Lymphocytic Leukemia ◽  
Phase 1 Study ◽  
Acceptable Safety Profile ◽  
Key Points

Key Points Otlertuzumab (formerly TRU-016) has modest single-agent activity in symptomatic treated and untreated CLL. Otlertuzumab demonstrates an acceptable safety profile, providing rationale for combination with other effective CLL therapies.

A phase 1 study of MORAb-009, a monoclonal antibody against mesothelin in pancreatic cancer, mesothelioma and ovarian adenocarcinoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14041-14041 ◽  
Author(s):  
D. K. Armstrong ◽  
D. Laheru ◽  
W. W. Ma ◽  
S. J. Cohen ◽  
M. Phillips ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Monoclonal Antibody ◽  
Cell Surface ◽  
Phase 1 ◽  
Single Agent ◽  
Primary Therapy ◽  
Cell Surface Antigens ◽  
Ovarian Adenocarcinoma ◽  
Primary Tumors

14041 Background: MORAb-009 is a monoclonal antibody that targets mesothelin, a cell surface adhesive protein overexpressed in pancreatic, ovarian, non-small cell lung carcinomas and mesothelioma and has minimal expression in normal tissue. The target is over-expressed by tumor cells. It was identified as one of the most prominent, differentially expressed cell surface antigens on pancreatic adenocarcinoma using SAGE of primary tumors vs. normal pancreatic tissue. In vitro studies show MORAb-009 to be effective in mediating cell killing by ADCC and inhibiting cell adhesion.. In xenograft models, MORAb-009 has single agent anti-tumor activity enhanced by the addition of chemotherapy. Toxicology studies show no toxicity in non-human primates and no significant binding to non-tumor tissues. Methods: Sequential cohorts of 3 patients received MORAb-009 intravenously on days 1, 8, 15 and 22 at doses of 12.5, 25, 50 and 100 mg/m2. Major inclusion criteria are the presence of a mesothelin-positive tumor with progression on primary therapy, acceptable organ function, ECOG PS 0–2, and measurable disease by CT. Safety pharmacology studies include chemistry, hematology, urinalysis and EKG. Tumors were re-imaged at day 35. Results: 11 patients have received MORAb-009 at doses up to 100 mg/m2. 6 patients had mesothelioma, 3 had pancreatic cancer and 2 had mesothelin-positive ovarian cancer. 4 patients exhibited grade 1 (3) or 2 (1) infusion reactions; no dose limiting toxicity was observed. A subject in the 50 mg/m2 cohort with pancreatic cancer who progressed on gemcitabine showed stable disease by CT and a drop in CA 19/9. Based on the response, this patient continues on extended MORAb-009 therapy. Enrollment to the final cohort of 200mgs/m2 is ongoing, as are pharmacokinetic and anti-MORAb-009 antibody analysis. Conclusion: MORAb-009, a monoclonal antibody against mesothelin is safe and well tolerated at doses up to 100 mg/m2. One subject with previously progressive pancreatic cancer had disease stabilization. In light of the positive preclinical data and safe clinical profile, this study supports further evaluation of the efficacy of MORAb-009 in mesothelin-positive tumors. No significant financial relationships to disclose.

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