Sustained Response Duration Seen after Treatment with Single Agent Blinatumomab (MT103/MEDI-538) in the Ongoing Phase I Study MT103- 104 in Patients with Relapsed NHL

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 267-267 ◽  
Author(s):  
Ralf C Bargou ◽  
Peter Kufer ◽  
Mariele Goebeler ◽  
Stefan Knop ◽  
Hermann Einsele ◽  
...  
Keyword(s):  
T Cell ◽  
Dose Level ◽  
Phase 1 ◽  
Single Agent ◽  
Cell Activity ◽  
Response Duration ◽  
Target Cells ◽  
Dose Escalation Study ◽  
Dose Levels ◽  
Fatal Sepsis

Abstract Introduction: Blinatumomab (MT103/MEDI-538), a BiTE antibody targeting the CD19 antigen, is a member of a novel class of molecules that redirect T cells for lysis of target cells. A Phase 1 dose escalation study is being conducted in patients with advanced NHL. Methods: Relapsed NHL patients requiring treatment were included. Most patients were pre-treated, with a median of 3 previous chemo/immunotherapy regimens. To date, 7 dose levels ranging from 0.0005 to 0.09 mg/m2/24 h have been tested. Blinatumomab was continuously infused as single agent over a period of 4–8 weeks. Objective responses were assessed by Cheson criteria and centrally reviewed. Results: To date 39 patients have been treated. Most common adverse events (AEs) included lymphopenia, pyrexia, and leukopenia. The majority of AEs (>95%) improved or resolved during treatment. Permanent treatment discontinuation due to AEs occurred in a total of 8 patients, of which 6 had fully reversible CNS events. One patient with a history of nearly fatal sepsis, pre-existing hypogammaglobulinemia and bone marrow affection by chemotherapy, experienced a fatal sepsis 5 weeks after treatment start. Dose-dependent activity was observed in mantle cell lymphoma, follicular lymphoma and CLL with responses observed in 11 out of 27 patients treated at doses of 0.015 mg/m2/24 h and higher. Five of those patients had complete and six had partial responses. At the dose level of 0.060 mg/m2/24 h, 7 out of 7 patients have shown objective responses. Beside one relapse after 14 months, no treatment failure has so far been observed for responders at dose levels of 0.030 mg/m2/24 h and 0.060 mg/m2/24 h. Five patients at these dose levels have ongoing responses for more than 6 months. Interestingly, partial remissions converted into complete remissions in two patients four weeks after end of infusion suggesting either reduction in lesion size due to efflux of a previously expanded T cell pool or prolonged T cell activity. Conclusions: Blinatumomab as single agent induced apparently durable responses in pre-treated B-NHL patients with the highest response rate at a dose level of 0.06 mg/m2/24 h. Recruitment is ongoing.

A Phase 1 Dose Escalation Study of a Fully Human, Antagonist Anti-CD40 Antibody, HCD122 (Formerly CHIR-12.12) in Patients with Relapsed and Refractory Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3575-3575 ◽  
Author(s):  
William Bensinger ◽  
Sundar Jagannath ◽  
Pamela S. Becker ◽  
Kenneth C. Anderson ◽  
Edward A. Stadtmauer ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Level ◽  
Ex Vivo ◽  
Phase 1 ◽  
Safety Evaluation ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Myeloma Cells ◽  
Dose Levels

Abstract HCD122 is a novel, fully human, IgG1 antagonistic monoclonal antibody targeting the CD40 receptor. This antibody blocks CD40-mediated signaling and is a potent mediator of antibody-dependent cellular cytotoxicity (ADCC). Previous preclinical investigation confirmed expression of CD40 on myeloma cells in the majority of patients and reported antitumor activity of HCD122 against multiple myeloma cells ex vivo (Tai, Y et al. Cancer Res2005; 65(13): 5898–5906). This ongoing phase 1 study will determine the maximum tolerated dose of CHIR-12.12 in multiple myeloma patients (pts) who are relapsed or refractory after at least one prior therapy. Planned dose levels are 1, 3 and 10 mg/kg administered IV once weekly for 4 weeks. Each dose group will enroll 3–6 pts to evaluate safety, pharmacokinetics (PK) and clinical response. To date, 9 pts have been treated at 2 dose levels: 3 pts at 1 mg/kg and 6 pts at 3 mg/kg. Median patient age is 65 yrs (46–81 yrs); median number of prior therapies is 3 (2–12). No dose limiting toxicity (DLT) occurred at the 1mg/kg dose level. At 3 mg/kg, 1 DLT of grade 4 thrombocytopenia occurred in 1 pt. No other grade 3 and 4 lab abnormalities and adverse events have been reported. In 7 pts with available data, infusions were well tolerated, with easily managed grade 1–2 toxicities, primarily chills (5 pts), nausea (3 pts), pyrexia (2 pts), and arthralgia (2 pts) mainly reported during the first infusion. Preliminary PK analysis showed more than dose proportional - increase in Cmax and AUC at the 3 mg/kg dose level compared to the 1 mg/kg dose level. At the 3 mg/kg dose, antibody accumulation occurred week-to-week; the mean Cmax after the fourth infusion on Day 22 was 126.1 mg/mL(range 52 – 195 ug/mL) and HCD122 levels were measurable up to Day 57 and in one patient up to Day 99. One week after the last 3 mg/kg dose, trough levels ranged from 28 to 109 mg/mL. Of the 3 pts at 1 mg/kg, one showed stable disease (SD) for >23 weeks and two had progressive disease (PD) by week 5. Of the 6 pts at 3 mg/kg, one had partial response (PR) at week 9 and was confirmed at week 15, one had SD for > 5 weeks, and 4 had PD at week 5. One pt with PD terminated the study before final safety evaluation, and must be replaced before assessment of the 3mg/kg dose level is complete. Thus, in preliminary studies, HCD122 appears to be safe and well tolerated to date at doses of 1 mg/kg and 3 mg/kg weekly for 4 doses and shows promising anti-myeloma activity. Enrollment is continuing to determine MTD.

Lenalidomide, Bortezomib, and Dexamethasone (Rev/Vel/Dex) as Front-Line Therapy for Patients with Multiple Myeloma (MM): Preliminary Results of a Phase 1/2 Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 187-187 ◽  
Author(s):  
Paul Richardson ◽  
Sundar Jagannath ◽  
Noopur Raje ◽  
Andrzej Jakubowiak ◽  
Sagar Lonial ◽  
...  
Keyword(s):  
Dose Level ◽  
Phase 1 ◽  
Single Agent ◽  
Safety Data ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Front Line ◽  
Dose Levels ◽  
Dose Reductions

Abstract Background: Bortezomib (VELCADE®, Vel) as a single agent and lenalidomide (Revlimid®, Rev) plus dexamethasone (Dex) are approved for the treatment of relapsed MM patients (pts) following ≥1 prior therapy. Rev/Vel±Dex is active and well tolerated in relapsed/refractory MM, and Rev/Dex and Vel/Dex have substantial activity in front-line MM. The aims of this phase 1/2 study were to determine the MTD of Rev/Vel/Dex in newly diagnosed MM pts, and to assess safety and efficacy. Methods: Pts received Rev 15–25 mg on d 1–14, Vel 1.0–1.3 mg/m2 on d 1, 4, 8, 11, and Dex 40/20 mg (cycles 1–4/5–8) on d 1, 2, 4, 5, 8, 9, 11, 12, for up to 8 21-d cycles, initially at 4 planned dose levels (Rev/Vel: 15/1.0, 15/1.3, 20/1.3, 25/1.3). Dose escalation proceeded (3-pt cohorts) depending on DLTs (G≥3 non-hematologic toxicity; G4 thrombocytopenia with platelets <10,000/mm3 on >1 occasion despite transfusion support; G4 neutropenia for >5 d and/or resulting in neutropenic fever; inability to receive cycle 2/d 1 dose due to drug-related toxicity). Based on safety data, dose level 4M was added with a reduced Dex starting dose (Rev/Vel 25/1.3, Dex 20 mg in all cycles). Toxicities were graded by NCI CTCAE v3.0. Pts with G>2 peripheral neuropathy (PNY) were excluded. Responses were assessed by modified EBMT and Uniform criteria. Pts with CR/nCR/VGPR/PR could proceed to ASCT after ≥4 cycles. Results: 33 pts (median age 56 yrs, 55% men, 84% IgG MM, 47% with ISS Stage II/III) have been enrolled to date in dose levels 1–4 and 4M, respectively, including 10 pts enrolled at the maximum planned dose (Dose Level 4M). Pts have received a median of 5 cycles; 9 pts have completed all 8 cycles. Two DLTs of G3 hyperglycemia due to high dose Dex were seen in dose level 4. Dose reductions in cycle 2 and beyond have occurred in dose levels 1–4 for Rev in 9 pts, Vel in 7 pts, and Dex in 17 pts, with 3 dose reductions having occurred in dose level 4M. Toxicities to date have been manageable. Only 1 G4 toxicity (thrombocytopenia) has been reported, plus 1 G3 DVT (reversed with LMWH), and no G≥3 PNY has been seen. The response rate across all dose cohorts (CR/nCR+VGPR+PR: subject to confirmation) is currently 89% in 25/28 evaluable pts, including 35% CR/nCR/VGPR. After median follow-up of 3 mos, median DOR, TTP, PFS, and OS have not been reached; all responders except 1 remain in remission, with 2 pts proceeding to ASCT. Conclusions: Rev/Vel/Dex is very active and well tolerated in newly diagnosed MM pts. The maximum planned dose has been reached at Rev 25 mg, Vel 1.3 mg/m2, and Dex 20 mg, with Phase 1 enrollment now complete using the lower dose of Dex. Enrollment to the Phase 2 component is ongoing.

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.

Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-δ,γ, in patients with relapsed/refractory lymphoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8518-8518 ◽  
Author(s):  
Steven M. Horwitz ◽  
Ian Flinn ◽  
Manish R. Patel ◽  
Anas Younes ◽  
Francine M. Foss ◽  
...  
Keyword(s):  
T Cell ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Safety And Efficacy ◽  
Early Results ◽  
Refractory Lymphoma ◽  
Grade 3

8518 Background: Phosphoinositide-3-kinases (PI3Ks) are pivotal in cell signaling and regulate a variety of cellular functions relevant to oncogenesis. IPI-145, a potent oral inhibitor of the PI3KEδ and PI3K-γ isoforms, is in clinical development for patients (pts) with hematologic malignancies. Early results in pts with relapsed/refractory lymphoma from an ongoing Phase 1 study are reported here. Methods: This dose-escalation study evaluates the safety, maximum tolerated dose (MTD), clinical activity, and pharmacokinetics (PK) of IPI-145. Expansion cohorts (EC) < MTD are allowed. IPI-145 is given orally twice daily (BID) in 28-day cycles. Tumor response is based on standard disease-specific criteria. Results: 55 pts have been dosed with IPI-145. PK, available through 50 mg BID, are linear with complete inhibition of PI3K-δ at doses > 15 mg BID and increasing suppression of PI3K-γ with increasing dose. In the 36 pts with lymphoma who received 15 mg to 75 mg BID, the median [range] number of cycles was 2.4 [0.1–10] and 67% remain on study. Treatment-related adverse events (TRAEs) occurred in 50% of pts with lymphoma. Neutropenia and increased ALT were the most common ≥ Grade 3 TRAEs (4 pts each) and were not associated with increasing dose. > Grade 3 ALT elevations were more common in lymphoma pts (18%) compared to non-lymphoma pts (5%). Among evaluable pts with lymphoma (n=27), early clinical activity was observed in T-cell (n=6, 1 CR, 1 PR, 1 SD) and aggressive/indolent B-cell (n=21, 2 CR, 9 PR, 5 SD) lymphoma pts at ≤ 75 mg BID. 92% of responses were observed by 3 months. Conclusions: IPI-145 appeared well tolerated and has shown clinical activity in pts with relapsed/refractory advanced B- and T-cell lymphoma across the range of doses examined. The single agent MTD has not been determined and dose escalation continues. Updated safety and efficacy data from pts with lymphoma enrolled in dose escalation or ECs evaluating 25 mg BID and a higher dose (< MTD) of IPI-145 will be presented. Clinical trial information: NCT01476657.

A first-in-human phase dose-escalation study of YH002, a recombinant humanized agonistic anti-OX40 IgG1 monoclonal antibody, in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14501-e14501
Author(s):  
Vinod Ganju ◽  
Adam Cooper ◽  
Kate Wilkinson ◽  
John J. Park
Keyword(s):  
Prostate Cancer ◽  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Cancer Breast ◽  
Dose Levels

e14501 Background: YH002 is a recombinant humanized IgG1 antibody that targets the human OX40 receptor. Preclinical studies have demonstrated the specificity, potency, and anti-cancer efficacy of YH002 in a comprehensive panel. The totality of nonclinical data supports progression of YH002 into clinical studies in adult patients (pts) with advanced solid tumors. Methods: This is an ongoing phase 1 dose-escalation study. Patients with advanced or metastatic refractory solid tumors received YH002 as single agent by IV administration at 0.01 to12.0 mg/kg dose levels every 21 days (Q3W), to evaluate the safety, tolerability and preliminary efficacy. An accelerated titration dose escalation design followed by a traditional 3+3 dose algorithm were utilized to assess dose-limiting toxicity (DLT) and identify MTD and/or RP2D. Tumor assessments were performed per RECIST v1.1 every 9 weeks. Results: By December 31 2020, six patients were enrolled and treated at escalating dose levels of 0.01 (n=1), 0.03 (n=1), 0.1 (n=1) and 0.3mg/kg (n=3), with tumor types including colon cancer, thymic cancer, prostate cancer, colorectal cancer, breast cancer and bladder cancer. Median treatment duration was 10.2 weeks (range 2 – 18). The median age of patients was 67 years old (range 47-78). These patients had progressed after a median of 2 prior lines of available standard therapy. As of data cutoff, no dose limiting toxicities (DLTs), no Grade (G) 3 or above adverse events (AE) or AEs leading to treatment discontinuation were reported. Drug-related adverse events (AEs) were all G1/2 events and occurred in 4 patients, including 8 G1 AEs (pneumonitis, rash, pruritus, arthralgia, myalgia, fatigue, lethargy, rash pruritic) and 3 G2 AEs (1 pneumonitis and 2 fatigue). Out of 5 patients having tumor assessment by RECIST, one pt with Thymic SCC at 0.3 mg/kg had best response of stable disease at week 9, one pt with prostate cancer at 0.1 mg/kg experienced Non-CR/Non-PD, and rest of 3 pts experienced progressive disease. Conclusions: These preliminary results demonstrate that YH002 was safe and tolerable up to 0.3mg/kg. Updated safety and antitumor activity will be presented. Clinical trial information: NCT04353102.

scholarly journals Safety and immunogenicity of the Ad26.COV2.S COVID-19 vaccine candidate: interim results of a phase 1/2a, double-blind, randomized, placebo-controlled trial

2020 ◽  
Author(s):  
Jerry Sadoff ◽  
Mathieu Le Gars ◽  
Georgi Shukarev ◽  
Dirk Heerwegh ◽  
Carla Truyers ◽  
...  
Keyword(s):  
Single Dose ◽  
T Cell ◽  
Adverse Events ◽  
Dose Level ◽  
Phase 1 ◽  
T Cell Responses ◽  
Cell Responses ◽  
Grade 3 ◽  
Efficacious Vaccine ◽  
Dose Levels

BACKGROUND The ongoing coronavirus disease (COVID)-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be controlled by an efficacious vaccine. Multiple vaccines are in development, but no efficacious vaccine is currently available. METHODS We designed a multi-center phase 1/2a randomized, double-blinded, placebo-controlled clinical study to assesses the safety, reactogenicity and immunogenicity of Ad26.COV2.S, a non-replicating adenovirus 26 based vector expressing the stabilized pre-fusion spike (S) protein of SARS-CoV-2. Ad26.COV2.S was administered at a dose level of 5x1010 or 1x1011 viral particles (vp) per vaccination, either as a single dose or as a two-dose schedule spaced by 56 days in healthy adults (18-55 years old; cohort 1a & 1b; n= 402 and healthy elderly >65 years old; cohort 3; n=394). Vaccine elicited S specific antibody levels were measured by ELISA and neutralizing titers were measured in a wild-type virus neutralization assay (wtVNA). CD4+ T-helper (Th)1 and Th2, and CD8+ immune responses were assessed by intracellular cytokine staining (ICS). RESULTS We here report interim analyses after the first dose of blinded safety data from cohorts 1a, 1b and 3 and group unblinded immunogenicity data from cohort 1a and 3. In cohorts 1 and 3 solicited local adverse events were observed in 58% and 27% of participants, respectively. Solicited systemic adverse events were reported in 64% and 36% of participants, respectively. Fevers occurred in both cohorts 1 and 3 in 19% (5% grade 3) and 4% (0% grade 3), respectively, were mostly mild or moderate, and resolved within 1 to 2 days after vaccination. The most frequent local adverse event (AE) was injection site pain and the most frequent solicited AEs were fatigue, headache and myalgia. After only a single dose, seroconversion rate in wtVNA (50% inhibitory concentration - IC50) at day 29 after immunization in cohort 1a already reached 92% with GMTs of 214 (95% CI: 177; 259) and 92% with GMTs of 243 (95% CI: 200; 295) for the 5x1010 and 1x1011vp dose levels, respectively. A similar immunogenicity profile was observed in the first 15 participants in cohort 3, where 100% seroconversion (6/6) (GMTs of 196 [95%CI: 69; 560]) and 83% seroconversion (5/6) (GMTs of 127 [95% CI: <58; 327]) were observed for the 5x1010 or 1x1011 vp dose level, respectively. Seroconversion for S antibodies as measured by ELISA (ELISA Units/mL) was observed in 99% of cohort 1a participants (GMTs of 528 [95% CI: 442; 630) and 695 (95% CI: 596; 810]), for the 5x1010 or 1x1011 vp dose level, respectively, and in 100% (6/6 for both dose levels) of cohort 3 with GMTs of 507 (95% CI: 181; 1418) and 248 (95% CI: 122; 506), respectively. On day 14 post immunization, Th1 cytokine producing S-specific CD4+ T cell responses were measured in 80% and 83% of a subset of participants in cohort 1a and 3, respectively, with no or very low Th2 responses, indicative of a Th1-skewed phenotype in both cohorts. CD8+ T cell responses were also robust in both cohort 1a and 3, for both dose levels. CONCLUSIONS The safety profile and immunogenicity after only a single dose are supportive for further clinical development of Ad26.COV2.S at a dose level of 5x1010 vp, as a potentially protective vaccine against COVID-19. Trial registration number: NCT04436276

Treatment of Patients with Non-Hodgkin Lymphoma (NHL) with CD19/CD3 Bispecific Antibody Blinatumomab (MT103): Double-Step Dose Increase to Continuous Infusion of 60 μg/m2/d Is Tolerable and Highly Effective

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2880-2880 ◽  
Author(s):  
Andreas Viardot ◽  
Mariele Goebeler ◽  
Jurgen S. Scheele ◽  
Gerhard Zugmaier ◽  
Richard Noppeney ◽  
...  
Keyword(s):  
T Cell ◽  
Dose Level ◽  
Bispecific Antibody ◽  
Single Agent ◽  
Objective Response ◽  
Response Duration ◽  
Single Step ◽  
Treatment Discontinuation ◽  
Double Step ◽  
Cell Ratio

Abstract Abstract 2880 Blinatumomab (MT103) is a single-chain bispecific antibody construct with specificity for CD19 and CD3 belonging to the class of bispecific T cell engager (BiTE®). We have previously reported that blinatumomab delivered as single agent to patients with relapsed NHL and B-precursor acute lymphoblastic leukemia by continuous intravenous (CIV) infusion over 4–8 weeks depleted peripheral B cells, expanded T effector cells, and resulted in clinical responses. In this phase I study 52 patients (41 males, 11 females) have been treated, 21 with FL, 21 with MCL and 10 with other subtypes of lymphoma (MZL, SLL, LPL, CLL). Patients have received a median of 3 prior regimens (range 1 to 12). Ninety percent of the patients had prior exposure to rituximab and 45% to fludarabine. Patients were treated at a dose range from 0.5 to 90 μg/m2/d. The most common adverse events (AEs) occurred early, were transient, reversible and did not require discontinuation of treatment. The most common clinical AEs regardless of causality were pyrexia (75%), headache (45%) and fatigue (37%). The most common laboratory abnormality AEs regardless of causality were lymphopenia (75%), leukopenia (57%), thrombocytopenia (39%), C-reactive protein increase (53%) and fibrin D dimer increase (37%). The medically most important AEs that resulted in permanent discontinuation were CNS events. Signs and symptoms observed included kinetic tremor, speech impairment, disorientation, apraxia and seizure. All CNS events were fully reversible without sequelae and no pathological findings by MRI imaging were reported. Out of the 52 patients treated, 9 had to discontinue treatment permanently in the first cycle due to these CNS events. At a dose of 90 μg/m2/d two DLTs were observed which were CNS events during the DLT period of the first 2 weeks of treatment. Therefore 60μg/m2/d is the currently recommended dose. A low B to T cell ratio (<1:8) determined by FACS analysis in peripheral blood was found to be a risk factor for CNS events. No CNS events requiring treatment discontinuation occurred in 32 out of 34 patients with a high B:T cell ratio (≥1:8) up to 60μg/m2/d. In the 18 patients with low B:T cell ratio, 7 had CNS events requiring treatment discontinuation. Patients with low B:T cell ratio were subsequently treated with an alternative dosing schedule in which reduced doses of either 5 and 15 μg/m2/d were sequentially administered for 1 week respectively followed by an increase to 60 μg/m2/d. First single-step dosing was applied. However, CNS events leading to treatment discontinuation were still observed. Therefore a double-step regimen was implemented; in the initial cohort of 3 patients with low B:T cell ratio there were no treatment discontinuations due to CNS events. Overall 18 patients with FL or MCL were treated with constant or step dosing regimens at or reaching 60 μg/m2/d dose level. Eight out of the 9 patients with constant dosing showed an objective response by Cheson criteria. All responders had a high B:T cell ratio. One patient with a low B:T cell ratio was discontinued due to a CNS AE. Six out of 9 patients with low B:T cell ratio enrolled for step dosing showed an objective response. One patient (single step dosing) discontinued treatment because of a CNS AE and 2 patients discontinued because of tumor progression. As of June 15th 2010, response duration ranged from 1 to 30+ months. Median for response duration was 26 months with 5 out of 14 responses ongoing. Table 1: Response evaluation in patients enrolled in 60 μg/m2/d cohorts. Dose Level Cohort Patients Complete Response Partial Response Overall Response FL MCL Total FL MCL Total FL MCL Total FL MCL Total 60 μg/m2/d Constant 6 3 9 2 1 3 4 1 5 6 2 8 5 or 15 then 60 μg/m2/d Single step 3 3 6 2 0 2 1 1 2 3 1 4 5/15/60 μg/m2/d Double Step 2 1 3 0 0 0 2 0 2 2 0 2 Total 11 7 18 4 1 5 7 2 9 11 3 14 These data confirm high single-agent activity of blinatumomab with long lasting remissions. Initial data with double step dosing demonstrate that this approach maintains clinical activity without discontinuations due to CNS AEs. Evaluation of safety and clinical efficacy of this uniform double step schedule including other subtypes of NHL is ongoing. Disclosure: Scheele: Micromet Inc.: Employment. Zugmaier:Micromet Inc.: Employment. Nagorsen:Micromet Inc.: Employment. Klinger:Micromet Inc.: Employment. Schmidt:Micromet Inc.: Employment. Klappers:Micromet. Inc: Employment. Kufer:Micromet Inc.: Employment. Bargou:Micromet Inc.: Consultancy.

scholarly journals 483 Initial safety results and immune responses induced by a novel human papillomavirus (HPV)-specific gorilla adenovirus immunotherapy vaccine, PRGN-2009, in patients with advanced HPV-associated cancers

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A513-A513
Author(s):  
Charalampos Floudas ◽  
Julius Strauss ◽  
Clint Allen ◽  
Renee Donahue ◽  
Caroline Jochems ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Single Agent ◽  
Hpv 16 ◽  
Dose Levels ◽  
Hpv 18

BackgroundPRGN-2009 is a novel gorilla adenovirus vaccine containing 35 non-HLA-restricted epitopes of HPV 16 and 18 which is being tested in an open-label, NCI-sponsored, single-center Phase I/II study alone and combined with the bifunctional TGF-β ”trap”/anti-PD-L1 fusion protein bintrafusp alfa (BA) (NCT04432597).MethodsFor the Phase I of the trial, eligible patients are adults with previously treated (checkpoint blockade allowed) recurrent/metastatic HPV-associated cancers. Objectives are to assess the safety and determine the recommended phase 2 dose (RP2D) of PRGN-2009 alone and combined with BA. Treatment followed a single-agent 3+3 dose escalation at two dose levels of PRGN-2009 (dose level 1: 1x1011 viral particle units (VPU), dose level 2: 5x1011 VPU) subcutaneously Q2W for 3 times, then Q4W for up to one year in total. After determination of RP2D, a combination cohort of 10 patients treated with PRGN-2009 at the RP2D combined with BA (1200 mg IV Q2W for 52 weeks) opened. Peripheral blood mononuclear cells collected from patients before and after vaccination with PRGN-2009 were stimulated with overlapping peptide pools and assessed by intracellular cytokine staining to identify HPV-16 and HPV-18 specific T-cells, as well as T-cells targeting cascade antigens not encoded by the vaccine.ResultsSix patients were enrolled in the single-agent PRGN-2009 dose-escalation phase (3 with cervical cancer, 2 with anal cancer, 1 with vaginal cancer). Observed adverse events were Grade 1-2 flu-like syndrome (headache, body aches), injection site reactions (erythema, pruritus, soreness, localized edema), fatigue, and rash. There were no dose limiting toxicities, and 5x1011 VPU was selected as RP2D. Four patients had stable disease as best response, (one ongoing, 10 months on treatment).T-cells targeting HPV-16 and/or HPV-18 were increased after vaccination in 100% of patients, with 3/6 (50%) developing HPV-16 T cells and 5/6 (83%) developing HPV-18 T cells. In some patients, the magnitude and breadth of HPV-16 and HPV-18 specific T cells were notably increased after repeated vaccination. T cells that target the cascade antigens brachyury and MUC1 were also increased in all patients evaluated. Multifunctional T-cell responses against all these antigens were also developed after vaccination in the majority of patients. No differences in immunogenicity were noted between the two dose levels. Enrollment is underway in combination with BA. Updated data will be presented.ConclusionsThe Phase 1 results demonstrate the safety of single-agent PRGN-2009 and induction of anti-HPV T-cell immune responses, supporting the hypothesis that PRGN-2009 could potentially induce anti-tumor effects in HPV-associated cancers.AcknowledgementsThis research was supported in part by the Intramural Research Program of the NIH, NCI.Trial RegistrationNCT04432597Ethics ApprovalApproved by the NIH IRB (Ref No 543876). All participants have given informed consent before taking part in the study.

scholarly journals Post-hoc Analysis of Pharmacodynamics and Single-Agent Activity of CD3xCD123 Bispecific Antibody APVO436 in Relapsed/Refractory AML and MDS Resistant to HMA or Venetoclax Plus HMA

2022 ◽  
Vol 11 ◽  
Author(s):  
Justin Watts ◽  
Tara L. Lin ◽  
Alice Mims ◽  
Prapti Patel ◽  
Cynthia Lee ◽  
...  
Keyword(s):  
T Cells ◽  
Bispecific Antibody ◽  
Cytotoxic T Cells ◽  
Phase 1 ◽  
Single Agent ◽  
Hematologic Malignancies ◽  
Dose Escalation Study ◽  
Post Hoc ◽  
Dose Levels

APVO436 is a recombinant bispecific antibody designed to direct host cytotoxic T-cells to CD123-expressing blast cells in patients with hematologic malignancies. APVO436 showed promising tolerability and single-agent activity in relapsed or refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The primary purpose of this post-hoc analysis was to evaluate the therapeutic and pharmacodynamic effects of APVO436 in 14 R/R AML/MDS patients who had failed treatment with hypomethylating agents (HMA) or venetoclax plus HMA prior to being enrolled in the APVO436 Phase 1 dose-escalation study that was recently completed. Eight of these 14 patients had R/R AML and had failed treatment with HMA (N=2) or venetoclax plus HMA (N=6). The remaining 6 patients had R/R MDS and had also failed treatment with HMA (N=5) or venetoclax plus HMA (N=1). They were treated with APVO436 at submicrogram dose levels &gt;0.08 mcg/kg that were active in preclinical NOD/SCID mouse xenograft models of AML. APVO436 activated patients’ T-cells as evidenced by reduced numbers of circulating CD123+CD34+ and CD33+CD34+ peripheral blasts. Single-agent activity was observed at dose levels ranging from 0.1 mcg/kg to 0.7 mcg/kg in 4 R/R AML patients (50%), including 3 patients with prolonged stable disease (SD) and one patient with complete remission (CR). Likewise, 3 MDS patients had SD (50%) and 3 additional MDS patients (50%) had a marrow CR at dose levels ranging from 0.1 mcg/kg to 0.8 mcg/kg. The median survival for the combined group of 14 R/R AML/MDS patients was 282 days. This early evidence of single-agent activity of APVO436 in R/R AML/MDS patients who failed HMA with or without venetoclax provides proof of concept supporting its in vivo immunomodulatory and anti-leukemic activity and warrants further investigation of its clinical impact potential.

Pharmacokinetics and Pharmacodynamics from a First-in-Human Phase 1 Dose Escalation Study with Antagonist Anti-CD40 Antibody, HCD122 (Formerly CHIR-12.12), in Patients with Relapsed and Refractory Chronic Lymphocytic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2837-2837 ◽  
Author(s):  
John C. Byrd ◽  
Ian W. Flinn ◽  
Khuda D. Khan ◽  
Thomas J. Kipps ◽  
Lea Aukerman ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Dose Level ◽  
Dose Escalation ◽  
Phase 1 ◽  
Antibody Therapy ◽  
Maximum Tolerated Dose ◽  
Lymphocytic Leukemia ◽  
Dose Escalation Study ◽  
Dose Cohort ◽  
Dose Levels

Abstract The CD40 antigen is expressed in most B-cell malignancies, including chronic lymphocytic leukemia (CLL), and represents an attractive target for antibody therapy. HCD122 is a high affinity, fully human IgG1 antagonistic anti-CD40 monoclonal antibody designed to exert antitumor activity as an inhibitor of CD40-ligand-mediated survival signals and as a potent mediator of antibody-dependent cellular cytotoxicity (ADCC). In this phase 1 study to determine maximum tolerated dose (MTD) in CLL, eligible patients (pts) include those with relapsed or refractory disease after prior fludarabine treatment and are assigned to receive one cycle of 4 weekly infusions of HCD122 at doses ranging from 0.3 to 10 mg/kg depending upon the dose cohort. A standard phase I design is used with each dose cohort enrolling 3–6 pts for evaluation of MTD, toxicity, pharmacokinetics (PK), and pharmacodynamics (PD). To date, 14 pts have been treated at 3 dose levels: 3 pts at 0.3 mg/kg, 4 pts at 1 mg/kg, and 7 pts at 3 mg/kg. Median patient age was 65 yrs (41–74 yrs); median number of prior therapies was 3 (2–11); median WBC at enrollment was 38.8 K/μ L (3.4–284 K/μ L). No dose limiting toxicity (DLT) occurred at the 0.3 and 1 mg/kg dose levels. At 3 mg/kg, streptococcal sepsis was reported in 1 pt after 2 study infusions and was considered DLT. Transient asymptomatic grade 3 or 4 elevation of amylase and/or lipase occurred in 2 subjects. In 9 pts with available data, infusions were associated with manageable grade 1–2 toxicity, primarily chills (7 pts), nausea (4 pts), and fever (3 pts) that was most predominant with the first infusion. PK analysis showed rapid clearance of HCD122 at the 0.3 and 1mg/kg dose levels, with no detectable levels at 2 and 7 days after infusion, respectively. PK data were available from 6 of 7 patients receiving 3mg/kg. These data indicated that some accumulation of HCD122 occurred at this dose level. Complete antigen saturation data were available for 2 of these subjects. Both showed sustained 100% saturation of antigen on peripheral CD5+CD19+ cells throughout the treatment period. Peripheral CD40+ CLL cells dropped transiently with a mean of 31% during each infusion in the majority of patients but the decreases were not maintained week-to-week. There were no substantive changes in NK or T-cell populations during therapy. In summary, HCD122 was safe and well tolerated up to the 3mg/kg dose level that is currently under evaluation. PK analysis to date suggests that levels higher than 3 mg/kg will be necessary to sustain levels of HCD122 in the expected therapeutic range, and dose escalation will continue to the maximum tolerated dose.

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