Denileukin Diftitox (ONTAK) Plus CHOP Chemotherapy in Patients with Peripheral T-Cell Lymphomas (PTCL), the CONCEPT Trial.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3449-3449 ◽  
Author(s):  
Francine Foss ◽  
Nelida Sjak-Shie ◽  
Andre Goy ◽  
Eric Jacobsen ◽  
Ranjana Advani ◽  
...  
Keyword(s):  
T Cell ◽  
Recombinant Dna ◽  
Nk Cell ◽  
Tumor Lysis Syndrome ◽  
Interleukin 2 ◽  
Clinical Activity ◽  
Chop Chemotherapy ◽  
First Line ◽  
Denileukin Diftitox ◽  
Grade 3

Abstract PTCL are an aggressive group of lymphomas comprising a number of histopathologic subtypes for which CHOP chemotherapy has been the standard first-line regimen at many centers. Denileukin diftitox (Dd) is a recombinant DNA-derived cytotoxic protein composed of diphtheria toxin fragments A and B and the full length sequence of human interleukin-2 (IL-2). Dd targets T-cells expressing the intermediate and high-affinity IL-2 receptor. Because the mechanism of action of Dd is distinct from traditional cytotoxic chemotherapy and Dd has exhibited minimal myelosuppression, we evaluated the safety, tolerability, and efficacy of combining Dd with CHOP as first-line therapy for patients with PTCL according to the REAL classification. (Pts with mycosis fungoides or Sezary syndrome were not included.) Dd was administered at 18 mcg/kg/day on Days 1 and 2 followed by CHOP on Day 3, and G-CSF support starting Day 4, every 3 weeks for up to 6 cycles. Evaluation of response is performed after every 2 cycles of treatment. Results: Forty-one pts, 18 male/23 female, have been enrolled to date, with a median age of 52. Ten pts are not evaluable for response: 5 discontinued due to an adverse event (AE) prior to assessment of response; 3 due to lack of measurable disease at baseline; and 2 are too early to evaluate. For the 31 response-evaluable patients, the overall response rate is 90%, with 71% (22/31) CR or CRu, 19% (6/31) PR, 6% (2/31) SD, and 3% (1/31) PD. Ten of 28 responders (36%) have progressed, with a median duration of response of 13 months. PTCL subtype No. of Patients No. evaluable Responses ORR PTCL-nos 20 15 3 CR, 5 CRu, 4 PR, 2 SD, 1 PD 80% Angioimmunoblastic 10 9 3 CR, 5 CRu, 1 PR 100% Anaplastic large cell 6 4 2 CR, 2 CRu 100% Enteric T-cell 2 1 1 CRu 100% Hepatosplenic 1 0 n/a n/a Nasal/nasal type T/NK cell 1 1 1 CRu 100% Subcutaneous panniculitic T-cell 1 1 1 PR 100% Toxicities have generally been grade 1–2, were transient, and caused few dose modifications. The most common have been fatigue (62%), nausea (44%), anemia (38%), sensory neuropathy (33%), hypoalbuminemia (33%), elevated ALT (30%), dyspnea (28%), thrombocytopenia (30%), leukopenia (28%), fever (25%), elevated AST (25%), lymphopenia (25%), and hyperglycemia (25%). Forty-three percent (17/40) of patients experienced one or more grade 3–4 hematological toxicities and 40% (16/40) of patients experienced one or more grade 3–4 non-hematological toxicities. Five patients discontinued the study due to AEs, all occurring prior to Cycle 2, for: infusion-related anaphylaxis; elevated LFTs; port-related staph sepsis; pneumonia; and a death possibly resulting from tumor lysis syndrome and rhabdomyolysis. Conclusion: The combination of Dd plus CHOP has a generally manageable safety profile and to date has exhibited promising clinical activity in PTCL.

Immunomodulatory effects of RXR rexinoids: modulation of high-affinity IL-2R expression enhances susceptibility to denileukin diftitox

Blood ◽  
2002 ◽  
Vol 100 (4) ◽  
pp. 1399-1403 ◽  
Author(s):  
Gullu Gorgun ◽  
Francine Foss
Keyword(s):  
T Cell ◽  
B Cell ◽  
Retinoic Acid Receptor ◽  
Interleukin 2 ◽  
Hematologic Malignancies ◽  
Clinical Activity ◽  
Immunomodulatory Effects ◽  
Denileukin Diftitox ◽  
High Affinity ◽  
T Cell Lymphomas

Rexinoids binding to both the retinoic acid receptor (RAR) and retinoid X receptor (RXR) families of rexinoid receptors have demonstrated clinical activity in hematologic malignancies and have been shown to mediate genes associated with both growth and differentiation. RXR rexinoids have demonstrated efficacy in the treatment of cutaneous T-cell lymphomas, but the mechanism of action is unclear. We explored the immunomodulatory effects of RAR and RXR rexinoids in human T- and B-cell leukemia cells and demonstrated that RXR rexinoids are capable of up-regulating high-affinity interleukin-2 receptor (IL-2R) expression. Exposure to 10−6 to 10−10 M bexarotene or Panretin for 48 hours was associated with increased expression of both the p55 and p75 subunits of the IL-2R in T-cell leukemias and p75 in B-cell leukemias. Furthermore, rexinoid exposure enhanced susceptibility of the cells to denileukin diftitox fusion toxin-targeting and -intoxicating cells expressing high-affinity IL-2R. These results suggest a rationale for combining rexinoids with IL-2R–targeted therapies in lymphoid malignancies as well as possibly in autoimmune diseases.

Inducible T-cell co-stimulatory (ICOS) receptor agonist, feladilimab (fela), alone and in combination (combo) with pembrolizumab (P): Results from INDUCE-1 urothelial carcinoma (UC) expansion cohorts (ECs).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4519-4519
Author(s):  
Arjun Vasant Balar ◽  
Victor Moreno ◽  
Eric Angevin ◽  
Hui Kong Gan ◽  
Maria Vieito ◽  
...  
Keyword(s):  
T Cell ◽  
Single Agent ◽  
Clinical Activity ◽  
Prior Therapy ◽  
Metastatic Setting ◽  
Duration Of Response ◽  
Prior Systemic Therapy ◽  
Grade 3 ◽  
Tumor Types

4519 Background: INDUCE-1 is a first-in-human trial evaluating fela, an IgG4 ICOS agonist non-T-cell depleting mAb, as monotherapy (mono) and in combo with P. ECs include tumor types, such as UC, with high ICOS expression and immunotherapy-favorable features. Fela induced IFNγ, increased PD-1/L1 expression, and enhanced antitumor activity in combo with PD-1 blockade nonclinically. We report preliminary efficacy, safety, and biomarker data of fela ± P in INDUCE-1 UC ECs. Methods: Eligible patients (pts) had recurrent/metastatic (R/M) UC of the upper or lower urinary tract, ≤6 prior systemic therapy lines in the advanced setting, measurable disease, and no active autoimmune disease. Pts received 0.3 or 1 mg/kg fela (mono EC; anti-PD-1/L1–experienced [exp] pts) or 0.3 mg/kg fela + 200 mg P (combo EC; anti-PD-1/L1–naïve pts) every 3 wks, up to 35 cycles until disease progression or unacceptable toxicity. Disease was assessed every 9 wks through wk 54, then every 12 wks. Archival and/or fresh biopsy tumor tissue was collected for biomarker analyses and safety assessed. Results: By Nov 6 2020, 13 anti-PD-1/L1–exp and 32 anti-PD-1/L1–naïve pts were evaluable in the mono and combo ECs, respectively. In the mono EC, median age was 69 yrs (range: 47–82), 92% of pts were male, and 85% received ≥2 prior therapy lines in the metastatic setting. In the combo EC, median age was 70 yrs (range: 42–84), 75% of pts were male, and 72% received ≥1 prior therapy line in the metastatic setting. In the mono EC, median duration of follow-up (mDoF) was 10.6 mo (range: 1.1–22.8); overall response rate (ORR) was 8% (1 partial response [PR]; 95% CI: 0.2, 36.0) with a duration of response (DoR) of 6.1 mo; disease control rate (DCR [response or stable disease for ≥9 wks]) was 23% (95% CI: 5.0, 53.8), and median overall survival (mOS) was 14.5 mo (95% CI: 2.8, NR), with 74% of pts alive at 6 mo. In the combo EC, mDoF was 9.6 mo (range: 0.9–28.3); ORR was 22% (7 PRs; 95% CI: 9.3, 40.0) with a median DoR of 8.3 months (range: 3.5–23.3+); DCR was 63% (95% CI: 43.7, 78.9), and mOS was 10.7 mo (95% CI: 5.2, 18.1), with 64% of pts alive at 6 mo. Grade ≥3 treatment-related AEs were reported for 0% and 9% of pts in the mono (N = 16) and combo (N = 44) safety populations, respectively. PD-L1 expression and ICOS-specific biomarkers are being evaluated, with promising trends observed in enrichment of clinical activity in preliminary analyses. Conclusions: Fela is the first ICOS agonist with reported single-agent activity in anti-PD-1/L1–exp relapsed/refractory UC. Fela + P in combo shows promising clinical activity and manageable safety in PD-1/L1–naïve R/M UC. Further study is warranted. Updated data to be presented. Funding: Study 204691 (NCT02723955) funded by GlaxoSmithKline in collaboration with Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA. Clinical trial information: NCT02723955.

scholarly journals Activation via the CD3 and CD16 pathway mediates interleukin-2- dependent autocrine proliferation of granular lymphocytes in patients with granular lymphocyte proliferative disorders

Blood ◽  
1991 ◽  
Vol 78 (12) ◽  
pp. 3232-3240 ◽  
Author(s):  
S Hoshino ◽  
K Oshimi ◽  
M Teramura ◽  
H Mizoguchi
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Nk Cell ◽  
Interleukin 2 ◽  
Cell Lineage ◽  
Cell Receptor ◽  
Cell Phenotype ◽  
Beta Chain ◽  
Alpha Beta ◽  
Granular Lymphocytes

Abstract Granular lymphocytes (GLs) in patients with GL-proliferative disorders (GLPDs) are known to express the interleukin-2 receptor (IL-2R) beta chain (p70–75) constitutively and to proliferate in response to stimulation with IL-2 via the beta chain. In this report, we found that the anti-CD3 monoclonal antibody (MoAb) OKT3 could induce the proliferation of GLs from patients with T-cell lineage GLPDs (T-cell receptor-alpha beta+/CD3+16+), but not that of natural killer (NK) cell lineage GLs (T-cell receptor-alpha beta-/CD3–16+). In contrast, the anti-CD16 MoAb 3G8 that reacts with NK-lineage GLs could induce the proliferation of these GLs but not that of GLs with a T-cell phenotype. Furthermore, the anti-CD16 MoAbs CLB FcR gran1 (VD2) and OK-NK, which react with both T- and NK-lineage GLs, induced the proliferation of GLs with both T- and and NK-cell phenotypes. The proliferative response induced via the CD3 or IgG Fc receptor III (Fc gamma RIII: CD16) pathway was shown to be associated with the IL-2-dependent autocrine pathway by various findings, including the induction of endogenous IL-2 production, the coexpression of the IL-2R alpha chain (p55) and the IL- 2R beta chain, and the inhibition of GL proliferation by anti-IL-2 or anti-IL-2R MoAb. These results suggest that GL proliferation is mediated at least partly through the IL-2-dependent autocrine pathway, and that the TCR/CD3 complex in T-cell phenotype GLs and the Fc gamma RIII in both T- and NK-cell phenotype GLs play a role in their activation in GLPDs.

scholarly journals Receptor-specific inhibition of bone marrow erythropoiesis by recombinant DNA-derived interleukin-2

Blood ◽  
1987 ◽  
Vol 69 (5) ◽  
pp. 1368-1375 ◽  
Author(s):  
SE Burdach ◽  
LJ Levitt
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Recombinant Dna ◽  
Interleukin 2 ◽  
Target Cells ◽  
Erythroid Progenitor ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
Dose Dependent

Abstract Interleukin-2 (IL-2) induces differential secretion of lymphokines by IL-2 receptor (IL-2R)-positive and IL-2R-negative T cells. We studied T cell IL-2R-specific modulation of adult bone marrow erythropoiesis by recombinant IL-2 (rIL-2). I3–2R were induced by CD3 T cell surface determinant-triggering and analyzed by cytofluorography. Bone marrow monocyte and T cell-depleted (NAB-T) target cells were assessed for early erythroid progenitor expression (BFU-E) in the presence of 0 to 10(3) U/mL of rIL-2, rIL-2 had no significant effect on BFU-E expression in the absence of T cells or in the presence of IL-2R- negative T cells. rIL-2 caused a dose-dependent inhibition (75% to 90%) of BFU-E in the presence of autologous IL-2R-positive T cells. The addition of anti-IL2-receptor antibody to cultures containing rIL-2 plus IL-2R-positive T cells entirely abrogated rIL-2-mediated inhibition of BFU-E. In the presence of rIL-2 (10(2) U/mL) production of interferon gamma (IF-gamma) by adult marrow CD3-triggered IL-2R- positive T cells was increased 37- to 125-fold compared to IL-2R- negative T cells. rIF-gamma caused a dose-dependent (88% +/- 17% at 10(3) U/mL) inhibition of adult BFU-E in the presence of CD3-triggered autologous T cells. rIL2-mediated inhibition of adult BFU-E in the presence of IL-2R-positive T cells was partially abrogated (52% +/- 16%) following addition of monospecific IF-gamma antibody. These results demonstrate (a) rIL-2 modulation of adult marrow erythropoiesis is selectively dependent upon both the presence or absence of autologous T cells and the IL-2R status of these T cells; and (b) rIL-2- induced inhibition of adult marrow erythropoiesis is mediated in part by release of IF-gamma from IL-2R-positive T cells.

scholarly journals Interleukin-induced increase in Ia expression by normal mouse B cells.

1984 ◽  
Vol 160 (3) ◽  
pp. 679-694 ◽  
Author(s):  
N W Roehm ◽  
H J Leibson ◽  
A Zlotnik ◽  
J Kappler ◽  
P Marrack ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Culture Supernatant ◽  
Recombinant Dna ◽  
Interleukin 2 ◽  
Relative Increase ◽  
Dependent Manner ◽  
Con A ◽  
Recombinant Dna Technology

The constitutive culture supernatant (SN) of the macrophage tumor line P388D1 (P388 SN) and the concanavalin A (Con A)-induced culture supernatant of the T cell hybridoma FS6-14.13 (FS6 Con A SN) were shown to contain nonspecific factors capable of inducing increased Ia expression by normal resting B cells in a dose-dependent manner. In six consecutive experiments the relative increase in Ia expression induced by P388 SN was 4.9 +/- 0.9, with FS6 Con A SN 10.7 +/- 1.5, and with a combination of both preparations 13.0 +/- 1.7. This increase in Ia expression was observed to occur in virtually all the B cells, reaching maximum levels within 24 h of culture. The interleukin-induced increase in B cell Ia expression occurred in the absence of ancillary signals provided by ligand-receptor Ig cross-linking and despite the fact that virtually all the control B cells, cultured in the absence of factors, remained in G0. These results suggest that functional receptors for at least some interleukins are expressed on normal resting B cells and their effects can be manifest in the absence of additional activating signals. The increased Ia expression induced by the nonspecific factor preparations was shown to be correlated with enhanced antigen-presenting capacity by the B cells to T cell hybridomas. The nature of the interleukins responsible for these effects remains to be definitively determined, however, the activity of FS6 Con A SN was shown to correlate with B cell growth factor activity and increased B cell Ia expression was not observed using interleukin 2 (IL-2) or interferon-gamma, prepared by recombinant DNA technology.

Pivotal Phase III Trial of Two Dose Levels of Denileukin Diftitox for the Treatment of Cutaneous T-Cell Lymphoma

2001 ◽  
Vol 19 (2) ◽  
pp. 376-388 ◽  
Author(s):  
Elise Olsen ◽  
Madeleine Duvic ◽  
Arthur Frankel ◽  
Youn Kim ◽  
Ann Martin ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Objective Response ◽  
T Cell Lymphoma ◽  
Therapeutic Interventions ◽  
Phase Iii ◽  
Cutaneous T Cell Lymphoma ◽  
Denileukin Diftitox ◽  
Grade 3 ◽  
Dose Levels

PURPOSE: The objective of this phase III study was to determine the efficacy, safety, and pharmacokinetics of denileukin diftitox (DAB389IL-2, Ontak [Ligand Phar-maceuticals Inc, San Diego, CA]) in patients with stage Ib to IVa cutaneous T-cell lymphoma (CTCL) who have previously received other therapeutic interventions. PATIENTS AND METHODS: Patients with biopsy-proven CTCL that expressed CD25 on ≥ 20% of lymphocytes were assigned to one of two dose levels (9 or 18 μg/kg/d) of denileukin diftitox administered 5 consecutive days every 3 weeks for up to 8 cycles. Patients were monitored for toxicity and clinical efficacy, the latter assessed by changes in disease burden and quality of life measurements. Antibody levels of antidenileukin diftitox and anti–interleukin-2 and serum concentrations of denileukin diftitox were also measured. RESULTS: Overall, 30% of the 71 patients with CTCL treated with denileukin diftitox had an objective response (20% partial response; 10% complete response). The response rate and duration of response based on the time of the first dose of study drug for all responders (median of 6.9 months with a range of 2.7 to more than 46.1 months) were not statistically different between the two doses. Adverse events consisted of flu-like symptoms (fever/chills, nausea/vomiting, and myalgias/arthralgias), acute infusion-related events (hypotension, dyspnea, chest pain, and back pain), and a vascular leak syndrome (hypotension, hypoalbuminemia, edema). In addition, 61% of the patients experienced transient elevations of hepatic transaminase levels with 17% grade 3 or 4. Hypoalbuminemia occurred in 79%, including 15% with grade 3 or 4 changes. Tolerability at 9 and 18 μg/kg/d was similar, and there was no evidence of cumulative toxicity. CONCLUSION: Denileukin diftitox has been shown to be a useful and important agent in the treatment of patients whose CTCL is persistent or recurrent despite other therapeutic interventions.

Sequential Phase II Studies of Flavopiridol by 72-Hour Continuous Infusion and 1-Hour Intravenous Bolus for the Treatment of Relapsed B-Cell Chronic Lymphocytic Leukemia: Results from CALGB Study 19805.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3485-3485
Author(s):  
John C. Byrd ◽  
Bercedis L. Peterson ◽  
Janice L. Gabrilove ◽  
Olatoyosi M. Odenike ◽  
Michael R. Grever ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Phase Ii ◽  
Tumor Lysis Syndrome ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Intravenous Bolus ◽  
Phase Ii Studies ◽  
Grade 3

Abstract Flavopiridol has in vitro activity in CLL and promotes apoptosis independent of p53 function or prior fludarabine exposure. We sought to determine if flavopiridol administered using two different schedules has activity in CLL. Patients with previously treated CLL were enrolled on two sequentially performed phase II studies. Patients in the first trial received flavopiridol (50 mg/m2 daily) as a continuous infusion (CI) over 72-hours every 2 weeks. Patients in the second trial received flavopiridol 50 mg/m2 as a 1-hour intravenous bolus (IVB) daily for three days repeated every 3 weeks. Patients received up to 6 (CI cohort) or 8 (IVB cohort) cycles of therapy. Fifteen patients enrolled in the 72-hour CI phase II trial; 6 (40%) had intermediate (Rai stage I or II) and 9 (60%) high (Rai stage III and IV) risk stages. No responses were noted in this group with 27% having stable disease (SD) and 73% progressive disease (PD). Thirty-six patients enrolled in the IVB study, with 13 (36%) having intermediate and 23 (64%) having high-risk disease. Four patients (11%) had partial responses, 19 (53%) SD, and 13 (36%) PD. The progression-free survivals for responders in the IVB study were 2.9, 3.2, 8.7, and 19.3 months. The median progression-free survival was 2.1 months (95% confidence interval [CI] 1.8 – 3.8) for patients in the CI study and 3.2 months (95% CI [2.5 – 7.4]) for the IVB study. The median overall survival was 27 months (95% CI [20–42]) for the CI study and 24 months (95% CI [18–31]) for the IVB study. Toxicity was manageable and included mainly myelosuppression (granulocytopenia and thrombocytopenia), infections, diarrhea and fatigue. Grade 3 and 4 toxicities were 20% and 27%, respectively, on the CI study and 39% and 33% on the IVB study. One patient on the IVB study had tumor lysis syndrome that was managed medically and did not require dialysis. There was one on-study death following a myocardial infarction on the IVB study. We conclude that flavopiridol has modest, schedule-dependent clinical activity in relapsed CLL and warrants future investigation utilizing alternative schedules of administration.

Efficacy and Safety of Denileukin Diftitox (Ontak®) in the Treatment of Cutaneous T-Cell Lymphoma (CTCL) According to CD25 Status.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2712-2712 ◽  
Author(s):  
Francine Foss ◽  
Madeleine Duvic ◽  
Larisa Geskin ◽  
Joseph Anderson ◽  
Pierluigi Porcu ◽  
...  
Keyword(s):  
Response Rate ◽  
Interleukin 2 ◽  
Median Number ◽  
Open Label ◽  
Denileukin Diftitox ◽  
Common Grade ◽  
Stage Ivb ◽  
Grade 3 ◽  
Number Of Cycles ◽  
Multi Center Study

Abstract Denileukin diftitox, an interleukin-2 (IL-2)-diphtheria toxin fusion protein, binds to and intoxicates cells expressing the medium (CD122, CD132) and high affinity (CD25, CD122, CD132) IL-2 receptor. Because its role in patients whose tumors tested negative for the CD25 component of the receptor had not been prospectively studied, we initiated a prospective, open label, multi-center study to evaluate the safety and efficacy of denileukin diftitox in CTCL patients according to CD25 status (CD25+ and CD25-). Patients with pathologically proven, persistent or recurrent CTCL Stages IB-IVA were treated with denileukin diftitox at a dose of 18 mcg/kg/day x 5 days every 21 days for up to 8 cycles. Expression of CD25 by tumor cells in skin biopsies was determined by IHC or flow cytometry at a central laboratory and investigators were blinded to CD25 status. Response was based on improvement in skin involvement by weighted skin assessment for lesion type (patch, plaque, tumor) and blood involvement based on quantitation of Sezary cells. Safety was evaluated based on reports of Grade 3 and 4 toxicities (NCI CTC version 2.0). Sixty-one pts were enrolled and treated with denileukin diftitox. Disease stages were: I-IIA (n=14), IIB (n=22), III (n=11) and IV (n=14). Eighteen (29.5%) had blood involvement. Fifty-seven pts completed at least one cycle of treatment and were evaluable for response. Four pts were excluded because they had Stage IVB (visceral) disease (n=2), did not have a post baseline skin assessment recorded (n=1), or did not complete the first cycle (n=1). The median number of cycles of denileukin diftitox was 4 (range 1–13). The overall response rate (CR+PR) was 53% (30/57, 95% CI 40–66%), with 2 CR. Of the 57 evaluable pts, tumor was CD25+ in 34 (70%), CD25- in 14 (25%) and unknown in 9. Response rate was similar in patients whose tumor tested CD25+ (56%, 95% CI: 39–73%), and CD25- (43%, 95% CI: 17–69%) (p=0.41). For the 61 patients the most common grade 3/4 toxicities included constitutional symptoms (11%) and metabolic/laboratory abnormalities (36%). One patient with significant cardiopulmonary disease died of myocardial infarction while on therapy. The frequency of grade 3/4 toxicities was similar in CD25+ 64% (23/36), vs CD25- 75% (12/16) (p=0.62). In conclusion, we found that 70% of the CTCL pts evaluated for this study tested CD25+ and that the response rates and safety profile of denileukin diftitox in CD25+ and CD25- patients were similar. These data support a role for denileukin diftitox in the treatment of CTCL regardless of CD25 status.

First Interim Results of a Phase I/II Study of Lenalidomide in Combination with Anti-PD-1 Monoclonal Antibody MDV9300 (CT-011) in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1838-1838 ◽  
Author(s):  
Yvonne A. Efebera ◽  
Ashley E Rosko ◽  
Craig Hofmeister ◽  
Joe Benner ◽  
Courtney Bakan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
T Cell ◽  
Partial Response ◽  
Phase I ◽  
Nk Cells ◽  
Disease Progression ◽  
Stable Disease ◽  
Nk Cell ◽  
Grade 3

Abstract Introduction: Multiple myeloma (MM) is associated with profound and widespread disarray of both the adaptive and innate arms of the immune system including loss of effector T cell function, humoral immune deficiency, and natural killer (NK) cell immunity. This immunosuppressive milieu is crucial to promoting disease progression. Standard treatment options (immunomodulators (IMIDs) and proteosome inhibitors, radiation, and high-dose corticosteroids) offer modest benefit, but also contribute to further immune suppression. Little is known regarding the mechanisms by which immune dysfunction and immunoevasion occur. Our group has characterized an important role for the programmed death receptor-1 (PD-1) / PD-L1 signaling axis in these processes. MDV9300 (formerly CT-011 / Pidilizumab) is a novel IgG1 humanized monoclonal antibody (mAb) that modulates the immune response through interaction with PD-1. Lenalidomide (Len) an IMID exerts efficacy in MM in part through enhancement of NK cell versus MM effect - an effect likely mediated through T cell production of interleukin (IL)-2. In our in-vitro study, pretreatment of NK cells with MDV9300 with or without Len enhanced immune complex formation between NK cells and MM tumor targets and also augmented NK cell activation and cytotoxicity against MM. We sought to determine the safety, tolerability and any early signs of efficacy in relapsed or refractory MM patients using MDV9300 in combination with Len. Methods: In the phase I portion, the primary endpoint is to determine the maximum tolerated dose (MTD) of the combination. Key eligibility criteria are relapsed or refractory disease but not progressed on Len 25 mg; ≥2 prior lines of therapy, absolute neutrophil count ≥ 1000/µL; Platelets ≥60,000/µL; and creatinine clearance of ≥ 40ml/min. Patients are treated with escalating doses of MDV9300 and Len utilizing a 3x3 escalation design (Table 1). If stable disease is the best response after 4 cycles, patients have the option of adding dexamethasone (20-40mg weekly). Len dose may be modified independently of MDV9300. Patients can receive a maximum of 12 cycles of therapy. Results: Twelve patients are evaluable to date. The median age was 68.5 (range 49-82) and the median time from diagnosis 4.98 years (range 1.54-12.62). At study entry, 67% had high risk cytogenetics (del 17p, complex karyotype, gain 1q) and the median number of prior treatment lines was 2 (range 2-11). 100% of patients had received prior Len, bortezomib and Dex, 50% alkylating agents (cyclophosphamide, oral melphalan, bendamustine), 75% autologous stem cell transplant, 25% pomalidomide and 33% carfilzomib. MDV9300 infusion has been well tolerated with only one grade 2 infusion related toxicity with sore throat. The patient received hydrocortisone with no further reaction observed. Grade 3/4 Anemia, neutropenia, and thrombocytopenia attributable to therapy have been seen in 25%, 23%, and 34% of patients, respectively. Other common grade 2-3 therapy related adverse events are fatigue (50%), anorexia (17%), and hypophosphatemia (17%). There has been no grade 3 or higher infection and no worsening of neuropathy from baseline. Len dose was reduced in 3 patients (25%) and increased in one. There has been no dose reduction in MDV9300. Dex 20 mg or less was added in 2 patients for muscle cramps and < PR after 3 cycles. To date 7 patients are off therapy; 1 due to grade 3 fatigue and 6 due to disease progression. Five patients continue on therapy at respective 12, 11, 9, 5 and 3 months. Responses to date have been 3 Very good partial response,1 partial response, 2 minimal response and 2 stable disease. Conclusion: The combination of steroid sparing MDV9300 and Len regimen has demonstrated an acceptable toxicity profile to date with evidence of anti-myeloma activity. This is the first reported combination anti-PD-1 based immune therapy for MM. Updated results will be presented at the meeting including the MTD dose for phase II. Table 1. MDV9300- mg/kg Intravenously given on day 3 every 28 days Lenalidomide- mg orally days 1-21 every 28 days DLT Evaluable DLTs Cohort 1 1.5 15 6 Grade 3 fatigue. Cohort extended to 6 Cohort 2 3 15 3 none Cohort 3 3 25 3 none Cohort 4 6 25 0 Acknowledgments: Drug has been provided by Medivation; The study is sponsored by the American Cancer Society Disclosures No relevant conflicts of interest to declare.

Phase II trial of a GM-CSF-producing and CD40L-expressing cell line combined with allogeneic tumor antigen as a novel vaccine for metastatic lung adenocarcinoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2559-2559
Author(s):  
Ben C. Creelan ◽  
Scott Antonia ◽  
David Noyes ◽  
Terri B. Hunter ◽  
George R. Simon ◽  
...  
Keyword(s):  
T Cell ◽  
Lung Adenocarcinoma ◽  
Cell Line ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Clinical Activity ◽  
Metastatic Lung ◽  
Grade 3

2559 Background: We created a vaccine in which irradiated allogeneic lung adenocarcinoma cells are combined with a bystander K562 cell line transfected with hCD40L and hGM-CSF. By recruiting and activating dendritic cells, we hypothesized the vaccine would induce tumor regression in metastatic lung adenocarcinoma. Methods: Intradermal vaccine was given every 14 days x3, followed by monthly x3. Cyclophosphamide (300 mg/m2 IV) was administered before 1st and 4th vaccines to deplete regulatory T-cells. All-trans retinoic acid was given (150/mg/m2/day) after 1st and 4th vaccines to enhance dendritic differentiation. Peripheral blood mononuclear cells (PBMCs) were collected at baseline and after each vaccination. T-cell activation profiles were analyzed by ELISpot assay and tested by generalized Wilcoxon for correlation to survival. Results: 24 participants were accrued at a single center from 10/2006 to 6/2008, with median age 64 and median of 3 previous lines of chemotherapy prior to entry. 20 were former smokers and 4 had brain metastases. A total of 101 vaccines were administered. Common toxicities of any grade were joint pain (79%) and fatigue (75%). Significant adverse events included a grade 3 hypotension and a grade 3 acute respiratory distress. No confirmed complete or partial radiologic responses were observed. Median overall survival (OS) was 8.0 mo (95% CI 3.5 – 12.5) and median time-to-progression was 2.4 mo (95% CI 0.3 – 4.6). Presence of HLA-A2 conferred reduced risk of progression (HR 0.37, 95% CI 0.14 -0.89, p=0.02) and trend to improved OS (HR 0.59, p = 0.06). Of 14 participants with evaluable PBMCs, 5 demonstrated sustained tumor peptide-specific T-cell activation after vaccination. Ex vivo peptide immune response correlated with improved OS compared to non-responders (23 vs. 7 mo, HR 0.48, p = 0.04). Conclusions: Vaccine administration was feasible and tolerable in a heavily pretreated population of metastatic lung cancer. These data suggest the vaccine has clinical activity in the subset with peptide-induced T-cell immune responses and warrants further investigation. A randomized trial of the vaccine is currently in development.

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