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.

scholarly journals Safety and Antitumor Activity of Acalabrutinib for Relapsed/Refractory B‐cell Malignancies: A Japanese Phase I Study

2021 ◽  
Author(s):  
Koji Izutsu ◽  
Kiyoshi Ando ◽  
Daisuke Ennishi ◽  
Hirohiko Shibayama ◽  
Junji Suzumiya ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
B Cell ◽  
Phase I Study ◽  
B Cell Malignancies

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.

First-in-human dose-escalation study of anti-EGFR ADC MRG003 in patients with relapsed/refractory solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3550-3550 ◽  
Author(s):  
Rui-hua Xu ◽  
Miao-Zhen Qiu ◽  
Yang Zhang ◽  
Xiao-Li Wei ◽  
Chaohong Hu
Keyword(s):  
Antitumor Activity ◽  
Adverse Events ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Single Agent ◽  
Antibody Drug Conjugate ◽  
Dose Escalation Study ◽  
Egfr Expression ◽  
Human Dose

3550 Background: MRG003 is a novel antibody drug conjugate (ADC) composed of a fully human anti-EGFR IgG1 monoclonal antibody conjugated to a microtubule disrupting agent monomethyl auristatin E (MMAE). MRG003 is presently being tested in an ongoing phase I study for safety, pharmacokinetics, and preliminary antitumor activity in patients (pts) with solid tumors (CTR20180310). Methods: In the phase I dose escalation study of a traditional (3+3) design, pts with relapsed or refractory cancers received single agent MRG003 once every 3 weeks (Q3W) for a maximum of 8 treatment cycles. The starting dose of MRG003 is 0.1 mg/kg, followed by 0.3, 0.6, 1.0, 1.5, 2.0, 2.5, and 3.0 mg/kg. Observations included adverse events (AEs), dose-limiting toxicity (DLT), and antitumor activity which is assessed every two cycles. Results: A total of twenty-two pts with colorectal (CRC, n = 15), nasopharyngeal (NPC, n = 3), head and neck (H&N, n = 2), esophageal (EC, n = 1), and duodenal (DC, n = 1) cancer were enrolled in the dose escalation. The median age of pts was 56.5 years. The MTD identified was 2.5 mg/kg. Commonly observed adverse events were anemia (50%), AST increase (41%), decreased appetite (41%), rash (36%), pruritus (36%), asthenia (36%), and proteinuria (32%). Majority of AEs were mild to moderate in severity. EGFR expression in patients’ tumor samples was determined retrospectively by a validated IHC method in a central laboratory. Nine out of 22 pts tested were EGFR positive. Among these 9 EGFR positive pts, one with NPC in the 2.5 mg/kg cohort had partial response, four had stable disease (one with H&N in the 1.5 mg/kg, one each with NPC and H&N in the 2.0 mg/kg, and one with EC in the 2.5 mg/kg cohorts). The disease control rate (DCR) at doses ≥1.5 mg/kg was 100% for the EGFR positive pts. Conclusions: The dose escalation study of MRG003 showed manageable safety profiles and encouraging preliminary antitumor activity in pts with EGFR-positive solid tumors. MRG003 is currently being evaluated as a single agent in phase I dose expansion cohorts to further assess safety, PK, and antitumor activity. Clinical trial information: CTR20180310 .

First-in-human phase I study of anti-HER2 ADC MRG002 in patients with relapsed/refractory solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS1101-TPS1101 ◽  
Author(s):  
Jin Li ◽  
Ye Guo ◽  
Junli Xue ◽  
Wei Peng ◽  
Xiaoxiao Ge ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Single Agent ◽  
Locally Advanced ◽  
Salivary Gland Cancer ◽  
Antibody Drug Conjugate ◽  
Her2 Positive

TPS1101 Background: MRG002 is an antibody drug conjugate (ADC) composed of a humanized anti-HER2 IgG1 monoclonal antibody conjugated to a microtubule disrupting agent monomethyl auristatin E (MMAE). MRG002 is presently being investigated in an ongoing phase I study for safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity in patients (pts) with solid tumors. Methods: MRG002 is evaluated as monotherapy for the treatment of pts with confirmed HER2 positive locally advanced or metastatic cancers, including breast cancer (BC), gastric cancer (GC), salivary gland cancer (SGC) and others. The primary objective is to determine the maximum tolerated dose (MTD) and a recommended phase II dose (RP2D). Secondary objectives include evaluation of PK, tumor response, and immunogenicity. In the dose escalation phase with “3+3” design, approximately 24 pts will be enrolled to identify MTD. The starting dose of MRG002 is 0.3 mg/kg, followed by 0.6, 1.2, 1.8, 2.2, 2.6, and 3.0 mg/kg. In the dose expansion phase, about 50 pts with HER2 positive advanced cancers will be enrolled to further evaluate the safety, antitumor activity, and PK at an appropriate confirmed dose. In this phase I study, each pt receives single agent MRG002 once every 3 weeks (Q3W) for a maximum of 8 treatment cycles. Pts with BC and GC should have HER2 positive advanced solid tumors per College of American Pathologists (CAP) guidelines. For other cancers, pts must have IHC status of 2+ or 3+, regardless of FISH results. Pts should have either failed or are ineligible for standard treatments. All pts must have at least 1 measurable lesion per RECIST 1.1. ECOG should be 0-1, and bone marrow, hepatic, renal, cardiac functions should be adequate. Observations include adverse events (AEs), dose-limiting toxicity (DLT), and antitumor activity, which is assessed every two treatment cycles. Further clinical trial details can be found on chinadrugtrials.org.cn (CTR20181778). Enrollment is ongoing since November 2018. Clinical trial information: CTR20181778 .

Zanidatamab (ZW25) in HER2-positive biliary tract cancers (BTCs): Results from a phase I study.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 299-299
Author(s):  
Funda Meric-Bernstam ◽  
Diana L. Hanna ◽  
Anthony B. El-Khoueiry ◽  
Yoon-Koo Kang ◽  
Do-Youn Oh ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Single Agent ◽  
Objective Response ◽  
Locally Advanced ◽  
Her2 Overexpression ◽  
Her2 Positive ◽  
Good Tolerability ◽  
Treatment Standard ◽  
Anti Tumor Activity

299 Background: Treatment options are limited for patients with unresectable, locally advanced or metastatic BTCs progressing after first line treatment. Standard second line chemotherapy yields objective response rates (ORR) of < 10% and median overall survival of these patients is < 6 months. Human epidermal growth factor receptor 2 (HER2) overexpression/ amplification is observed in 5–19% of BTCs. Zanidatamab is a bispecific HER2-targeted antibody that has demonstrated durable single agent activity with good tolerability in a range of HER2-overexpressing cancers. Methods: In the expansion cohort of this phase I study (NCT02892123), the primary objective is to characterize safety and tolerability of zanidatamab and secondary objectives include evaluation of anti-tumor activity. This cohort includes BTC patients with centrally confirmed HER2 overexpression (immunohistochemistry [IHC] 3+ or IHC 2+/ fluorescence in situ hybridization [FISH]+), disease progression after standard of care therapy, and measurable disease per RECIST 1.1. Zanidatamab is administered at the previously identified recommended dose of 20 mg/kg every 2 weeks (Q2W). Tumors are assessed every 8 weeks (response confirmed at ≥ 4 weeks). Results: As of the data cutoff date (Jul 28, 2020), 20 patients (median age: 63 years [range, 42–78]) with BTC (11 gallbladder cancers, 5 intra- and 4 extra-hepatic cholangiocarcinomas) have been treated with zanidatamab. The median number of prior systemic therapies was 2.5 (range, 1–8), including five patients who had received prior HER2-targeted therapy (trastuzumab). Fourteen (70%) patients experienced zanidatamab-related adverse events (AEs), all of which were grade 1 or 2 in severity. The most common (occurring in ≥ 20%) zanidatamab-related AEs were diarrhea (n = 9) and infusion-related reactions (n = 6). A single treatment-related serious AE of grade 2 fatigue was reported in one patient. Among patients evaluable for response (n = 17), the confirmed ORR was 47% (n = 8; 95% confidence interval [CI]: 23, 72), the disease control rate was 65% (n = 11; 95% CI: 38, 86) and the median duration of response was 6.6 months (95% CI: 3.2, not estimable). Conclusions: Zanidatamab is well tolerated with promising and durable anti-tumor activity in patients with HER2 overexpressing BTC. Based on these data, zanidatamab is now being evaluated in an ongoing global Phase 2b study in patients with advanced HER2+ BTC that have progressed after treatment with a gemcitabine-containing regimen (NCT04466891). Clinical trial information: NCT02892123.

A Phase I Trial of the Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib (PCI-32765), in Combination with Rituximab (R) and Bendamustine in Patients with Relapsed/Refractory Non-Hodgkin's Lymphoma (NHL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1643-1643 ◽  
Author(s):  
Kristie A. Blum ◽  
Beth Christian ◽  
Joseph M. Flynn ◽  
Samantha M. Jaglowski ◽  
Jeffrey Alan Jones ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Dose Level ◽  
Research Funding ◽  
Phase I Study ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Irreversible Inhibitor ◽  
Grade 3 ◽  
Dose Reductions

Abstract Abstract 1643 Introduction: Ibrutinib is an orally available, irreversible inhibitor of BTK, a downstream protein in the B-cell receptor signaling pathway critical for normal B-cell development. In a phase I study in patients with relapsed B-cell malignancies (Fowler ASH 2010), the overall response rate (ORR) was 43%, with responses observed in patients with relapsed mantle cell (MCL), diffuse large B-cell (DLBCL), follicular (FL), and marginal zone lymphoma (MZL). In a phase II single agent study in MCL (Wang ASH 2011), ORR was 67% with several responding patients remaining on ibrutinib over 1 year. Rituximab (R) and bendamustine is a highly active regimen with ORR ranging from 52–92% in patients with relapsed/refractory NHL. This phase I study was designed to determine the maximum tolerated dose, dose limiting toxicity (DLT), toxicities, and preliminary efficacy of R-bendamustine in combination with ibrutinib in patients with relapsed/refractory NHL. Methods: Eligibility included patients with relapsed/refractory FL, MZL, MCL, transformed NHL, and DLBCL, and patients with previously untreated MCL not candidates for autologous stem cell transplantation (ASCT). ANC ≥1000/mm3, platelets ≥50,000/mm3, and creatinine ≤ 2.0 mg/dL were required at study entry. Prior ASCT, rituximab, bendamustine, and ibrutinib were permitted. Treatment consisted of R 375 mg/m2 day 1, bendamustine 90 mg/m2days 1 and 2, and escalating doses of ibrutinib (280 mg or 560 mg) days 1–28 every 28 days for 6 cycles. Six patients were enrolled at each dose level. Responding patients could continue ibrutinib alone after cycle 6 until disease progression or unacceptable toxicity. Pegfilgrastim was permitted for patients with grade 4 neutropenia during cycles 1–6. Response was assessed after cycles 3 and 6 by International Harmonization Criteria (Cheson, JCO 2007). Results: Eleven patients (9 males) with a median age of 72 (range 45–84) previously treated with a median of 3 prior therapies (range 0–10) were enrolled. Six patients were refractory to their most recent therapy, 4 patients had prior ASCT, 2 patients had received prior bendamustine, and no patients had prior ibrutinib. Other characteristics included stage III-IV disease in 82%, extranodal involvement in 64%, elevated IPI ≥3 in 55%, bulky adenopathy ≥5 cm in 45%, B-symptoms in 45%, and elevated LDH in 36%. Histologies included MCL (n=3), DLBCL (n=3, all germinal center origin by Hans immunohistochemical criteria), transformed NHL (n=2), FL (n=2), MZL (n=1). Nine patients completed two or more cycles of therapy (median 3, range 1–6) with 280 mg of ibrutinib (n=6) and 560 mg of ibrutinib (n=3). Two patients who discontinued therapy prior to completing cycle 1 for progressive disease (PD) at 280 mg and 560 mg of ibrutinib, respectively, were replaced. Six patients continue to receive protocol treatment. The 5 patients off study included the 2 patients with DLBCL and transformed NHL who were replaced for PD prior to completing cycle 1, 2 patients with DLBCL and PD after cycles 3 and 4, and 1 patient with MCL receiving 280 mg ibrutinib with R-bendamustine who discontinued due to grade 3 neutropenia lasting > 14 days after cycle 4. No DLTs have been observed. Grade 3–4 events included lymphopenia (64%), neutropenia (27%), thrombocytopenia (18%), pancreatitis (9%), vomiting (9%), shingles (9%), and rash (9%). Dose reductions from 280 mg ibrutinib to 140 mg were required in 3 patients for grade 3 thrombocytopenia, pancreatitis, and rash. Bendamustine dose reductions to 60 mg/m2were required in 1 patient for grade 3 thrombocytopenia. ORR was 38% in 8 evaluable patients, with 3 patients currently receiving protocol treatment who have not yet undergone restaging scans. Responses included 2 complete responses and 1 partial response in the 3 patients with MCL. Conclusions: Combined ibrutinib with R-bendamustine appears well tolerated without unexpected toxicity and with preliminary activity in patients with previously untreated and relapsed MCL. Three additional patients will be accrued to the 560 mg dose level and expansion cohorts examining this combination specifically in patients with FL, DLBCL, and MCL are planned. Disclosures: Blum: Pharmacyclics: Research Funding. Off Label Use: Ibrutinib is not approved for the treatment of NHL. Jaglowski:Pharmacyclics: Research Funding. Maddocks:Pharmacyclics: Research Funding. Byrd:Pharmacyclics: Research Funding.

Phase I Study of Intravenous PI3K Inhibitor Bay 80–6946: Preliminary Activity in Patients with Relapsed Non-Hodgkin Lymphoma (NHL) Treated in an MTD Expansion Cohort

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3704-3704 ◽  
Author(s):  
Amita Patnaik ◽  
Ramesh K Ramanathan ◽  
Leonard Joseph Appleman ◽  
Anthony W Tolcher ◽  
James M Mountz ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Clin Oncol ◽  
Research Funding ◽  
Single Agent ◽  
Pi3k Inhibitor ◽  
Pharmacokinetic Parameters ◽  
Clinical Activity ◽  
18Fdg Pet ◽  
Expansion Cohort

Abstract Abstract 3704 Background: BAY 80–6946 is a potent and highly selective, reversible, pan-Class I phosphatidylinositol-3-kinase (PI3K) inhibitor, with broad antitumor activity in a panel of preclinical models including both indolent and aggressive NHL. Even in the absence of PIK3CA mutations, the PI3 pathway has been demonstrated to be constitutively activated in the majority of B-cell lymphomas. BAY 80–6946 was more potent than CAL-101 in inhibiting the in vitro growth of a panel of leukemia/lymphoma cell lines. Methods: In a phase I dose escalation study, BAY 80–6946 was previously reported to be tolerated as a 1-hr infusion at a dose of 0.8 mg/kg (MTD) on days 1, 8 and 15 every 28 days (J Clin Oncol 29: 2011 suppl; abstr 3035). Additional patients were treated in MTD expansion cohorts to assess safety, PK, biomarkers and clinical benefit in selected patient populations, including one expansion cohort in NHL. Based upon the beneficial clinical responses observed in 5 follicular lymphoma (FL) patients (J Clin Oncol 30: 2012 suppl; abstr 3019), the NHL cohort was expanded up to a total of 12 patients. Samples were collected for pharmacokinetic analyses. Exploratory analyses of changes in several plasma proteins, chosen with emphasis on B-cell homing/survival, were performed. Response was assessed using International Working Group response criteria, including 18FDG-PET. Results: To date, 9 NHL patients have been enrolled (FL, n=6, DLBCL, n=3). There were 5 females/4 males with a median age of 72 years (range, 40–84). Among these 9 patients, 5 (56%) had received 3 or more prior regimens. All have received prior Rituximab and 6/9 prior anthracycline and 4/9 prior Bendamustine. Eight patients were evaluable for safety and tolerability. The most frequently drug-related adverse events reported in >20% of the patients were hyperglycemia, nausea, diarrhea, anemia, mucositis, and fatigue. Interstitial pneumonitis was observed in 2 patients with FL. Both patients responded to corticosteroids and one continued on treatment at full dose without recurrence of the pneumonitis. The pharmacokinetic parameters of BAY 80–6946, including the Cmax and AUC, were consistent with those seen in solid tumour patients. Changes in the plasma levels of CXCL13 and BAFF were observed in subjects treated with BAY 80–6946. Median time on study was 129 days (3–487). Best response in 6 evaluable patients (FL, n=5, DLBCL, n=1) was 5 PR and 1 PD, all 5 evaluable FL patients achieving a PR, the longest of which is >16 months. Pharmacodynamic effects were demonstrated with significant lymphoma shrinkage observed as early as 48 hours after the first dose of BAY 80–6946 on 18FDG-PET/CT in both FL and DLBCL patients. Conclusions: In this MTD expansion cohort study in NHL lymphoma, BAY 80–6986 was generally well tolerated and showed very promising clinical activity in NHL patients. Updated clinical, PK and pharmacodynamic results will be presented. Based on these preliminary results, further clinical development as a single agent or in combination regimens in NHL is warranted. Disclosures: Patnaik: Bayer: Research Funding. Ramanathan:Bayer: Research Funding. Appleman:Bristol-Myers: Research Funding; Bayer Pharmaceuticals: Research Funding; AstraZeneca: Research Funding; Amgen: Research Funding; Abbott: Research Funding; Cougar Biotechnology/Ortho Biotech: Research Funding; Medivation: Research Funding; Excelixis: Research Funding. Beerham:Bayer: Research Funding. Weiss:Bayer: Honoraria; Roche/Ventana: Honoraria; Merrimack: Honoraria; Cephalon: Honoraria; Eli Lilly: Honoraria; Cytrx: Consultancy; Genentech: Speakers Bureau; Pfizer: Speakers Bureau; Caris Life Sciences: Speakers Bureau; Bayer: Research Funding. Rajagopalan:Bayer Pharmaceuticals: Employment. Jeffers:Bayer Pharmaceuticals: Employment. Kelly:Bayer Pharmaceuticals: Employment. Genvresse:Bayer Pharma AG: Employment.

scholarly journals Safety and Clinical Activity of a Combination Therapy Comprising Two Antibody-Based Targeting Agents for the Treatment of Non-Hodgkin Lymphoma: Results of a Phase I/II Study Evaluating the Immunoconjugate Inotuzumab Ozogamicin With Rituximab

2013 ◽  
Vol 31 (5) ◽  
pp. 573-583 ◽  
Author(s):  
Luis Fayad ◽  
Fritz Offner ◽  
Mitchell R. Smith ◽  
Gregor Verhoef ◽  
Peter Johnson ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Single Agent ◽  
Objective Response ◽  
B Cell Lymphoma ◽  
Response Rates ◽  
Low Grade ◽  
Inotuzumab Ozogamicin ◽  
Non Hodgkin Lymphoma

Purpose Inotuzumab ozogamicin (INO) is an antibody-targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. We performed a phase I/II study to determine the maximum-tolerated dose (MTD), safety, efficacy, and pharmacokinetics of INO plus rituximab (R-INO) for treatment of relapsed/refractory CD20+/CD22+ B-cell non-Hodgkin lymphoma (NHL). Patients and Methods A dose-escalation phase to determine the MTD of R-INO was followed by an expanded cohort to further evaluate the efficacy and safety at the MTD. Patients with relapsed follicular lymphoma (FL), relapsed diffuse large B-cell lymphoma (DLBCL), or refractory aggressive NHL received R-INO every 4 weeks for up to eight cycles. Results In all, 118 patients received one or more cycles of R-INO (median, four cycles). Most common grade 3 to 4 adverse events were thrombocytopenia (31%) and neutropenia (22%). Common low-grade toxicities included hyperbilirubinemia (25%) and increased AST (36%). The MTD of INO in combination with rituximab (375 mg/m2) was confirmed to be the same as that for single-agent INO (1.8 mg/m2). Treatment at the MTD yielded objective response rates of 87%, 74%, and 20% for relapsed FL (n = 39), relapsed DLBCL (n = 42), and refractory aggressive NHL (n = 30), respectively. The 2-year progression-free survival (PFS) rate was 68% (median, not reached) for FL and 42% (median, 17.1 months) for relapsed DLBCL. Conclusion R-INO demonstrated high response rates and long PFS in patients with relapsed FL or DLBCL. This and the manageable toxicity profile suggest that R-INO may be a promising option for CD20+/CD22+ B-cell NHL.

A phase I study of the safety, tolerability, pharmacokinetics, and immunoregulatory activity of urelumab (BMS-663513) in subjects with advanced and/or metastatic solid tumors and relapsed/refractory B-cell non-Hodgkin’s lymphoma (B-NHL).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS3107-TPS3107 ◽  
Author(s):  
Ignacio Melero ◽  
Tara C. Gangadhar ◽  
Holbrook Edwin Kohrt ◽  
Neil Howard Segal ◽  
Theodore Logan ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
B Cell ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Hodgkin’S Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Advanced Solid Tumors ◽  
Non Hodgkin's Lymphoma

TPS3107 Background: CD137 (4-1BB) is a costimulatory molecule that belongs to the TNF superfamily. It is upregulated on activated lymphocytes, NK cells and dendritic cells and plays an important role in the potentiation of antigen-specific immune responses in T-cell directed therapy as well as in antibody-dependent cell-mediated cytotoxicity. Urelumab is an agonistic antibody targeting CD137 which has demonstrated antitumor activity against a variety of cancers in pre-clinical and clinical studies. We describe a phase I study to investigate the clinical and biologic effects of treatment with urelumab in patients with advanced solid tumors and B-cell non-Hodgkin’s lymphoma (B-NHL). Methods: This phase I study (n=70) will include dose escalation (Part 1) using a 6+9 design, cohort expansion (Part 2), and tumor-specific cohort expansion (Part 3). In Part 1, successive cohorts of pts with advanced solid tumors will be treated as follows: Cohort 1 (0.1 mg/kg q3weeks) and Cohort 2 (0.3 mg/kg q3weeks). In Part 2, both cohorts (1 +2) will expand to 20 patients with advanced solid tumors. In Part 3, additional tumor-specific cohorts with B-NHL, colorectal cancer, and head and neck cancer (10 subjects each) will be enrolled at the highest tolerated dose. The primary objective of this study is to evaluate the safety and to define the MTD of the respective doses of 0.1 and 0.3 mg/kg administered every 3 weeks with special attention to hepatic toxicity. Secondary objectives include assessment of the preliminary antitumor activity, pharmacokinetics, and immunogenicity. Exploratory objectives include investigation of the immunoregulatory activity in peripheral blood and paired tumor biopsy specimens and associations with clinical outcome. Part 1 (dose escalation) has been completed without any DLTs. Clinical trial information: NCT01471210.

Phase I/II Trial of Tremelimumab in Patients With Metastatic Melanoma

2009 ◽  
Vol 27 (7) ◽  
pp. 1075-1081 ◽  
Author(s):  
Luis H. Camacho ◽  
Scott Antonia ◽  
Jeffrey Sosman ◽  
John M. Kirkwood ◽  
Thomas F. Gajewski ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Metastatic Melanoma ◽  
Phase Ii ◽  
Cytotoxic T Lymphocyte ◽  
Single Agent ◽  
Objective Response ◽  
Complete Response ◽  
Dosing Regimen ◽  
Grade 3

PurposeCytotoxic T lymphocyte-associated antigen 4 (CTLA4) blockade with tremelimumab (CP-675,206), a fully human anti-CTLA4 monoclonal antibody, was tolerated and demonstrated antitumor activity in a single dose, dose-escalation phase I trial in patients with solid tumors. This phase I/II trial was conducted to examine safety of multiple doses of tremelimumab, to further assess efficacy, and to identify an appropriate dosing regimen for further development.Patients and MethodsTwenty-eight patients with metastatic melanoma received monthly intravenous infusions of tremelimumab at 3, 6, or 10 mg/kg for up to 1 year to determine recommended monthly phase II dose. During phase II, 89 patients received tremelimumab 10 mg/kg once every month or 15 mg/kg every 3 months.ResultsNo dose-limiting toxicity was observed in phase I once every month dosing. In phase II, 8 (10%) of 84 response-assessable patients attained objective antitumor responses; best overall objective response was one complete response and three partial responses in each dosing regimen. Most responses were durable (range, 3 to 30+ months). Most frequent treatment-related adverse events (AEs) were diarrhea, rash, and pruritus. Frequency of grade 3/4 AEs was 13% in the 15 mg/kg every 3 months arm and 27% in the 10 mg/kg once every month. Serious AEs were also less frequent in the 15 mg/kg once every 3 months cohort (9% v 23% in 10 mg/kg arm).ConclusionMultiple infusions of tremelimumab were generally tolerable and demonstrated single-agent antitumor activity. Both phase II regimens generated durable tumor responses. Based on its more favorable safety profile, 15 mg/kg every 3 months was selected for further clinical testing.

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