CEA is expressed in >90% of pancreatic cancers (PC) and may be an appropriate immunotherapy target. CEA is poorly immunogenic due to immune tolerance; CAP1-6D, an altered peptide ligand can help ...bypass tolerance. We conducted a pilot randomized phase I trial in PC patients to determine the peptide dose required to induce an optimal CD8(+) T cell response.
Patients with a PS 0-1, HLA-A2+ and CEA-expressing, previously-treated PC were randomized to receive 10 μg (arm A), 100 μg (arm B) or 1000 μg (arm C) of CEA peptide emulsified in Montanide and GM-CSF, given every 2 weeks until disease progression.
Sixty-six patients were screened and 19 enrolled of whom 14 received at least 3 doses of the vaccine and thus evaluated for the primary immunologic endpoint. A median of 4 cycles (range 1-81) was delivered. Median and mean peak IFN-γ T cell response by ELISPOT (spots per 10(4) CD8(+) cells, Arm A/B/C) was 11/52/271 (A vs. C, p = 0.028) for medians and 37/148/248 (A vs. C, p = 0.032) for means. T cell responses developed or increased in 20%/60%/100% of pts in Arms A/B/C. Seven of the 19 patients remain alive at a minimum 32 months from trial initiation, including three with unresectable disease.
The T cell response in this randomized phase I trial was dose-dependent with the 1 mg CEA peptide dose eliciting the most robust T cell responses. A signal of clinical benefit was observed and no significant toxicity was noted. Further evaluation of 1 mg CEA peptide with stronger adjuvants, and/or combined with agents to overcome immune inhibitory pathways, may be warranted in PC pts.
ClinicalTrials.gov NCT00203892.
Abstract 37
The primary objective of CALGB 100104 was to determine if maintenance lenalidomide would prolong time to progression (TTP) after single AHSCT for multiple myeloma.
Stage I-III multiple ...myeloma, ≤ 1 year from diagnosis, ≥ 2 months of induction with stable disease or better and age < 70 years. AHSCT regimen was melphalan 200 mg/m2. Patients (pts) with stable disease or better were randomized double-blinded at day 100–110 post-AHSCT to lenalidomide or placebo, after stratification by diagnostic β2-microglobulin (β2M) level and prior thalidomide or lenalidomide therapy. Starting dose was 10 mg/day, escalated to 15 mg/day after 3 months and continued until disease progression. Drug was stopped and dose reduced according to the development of toxicity. Drug was held for ≥ Gr 3 toxicity, restarted at resolution to ≤ Gr 2 and de-escalated by 5 mg or maintained as tolerated at 15, 10, 5 mg daily or 5 mg daily for 21 of 28 days per month. All pts required some form of anticoagulation including aspirin, warfarin or heparin compounds. There was no consolidation therapy.
568 pts were enrolled before AHSCT (04/15/05-07/03/09) from 47 centers. Of 108 pts (19%) not randomized, reasons were: progressive disease/no response 16%, adverse events (AEs) 5%, died during therapy 2%, refusal 26 %, other disease 1%, other therapy 4 %, other reasons 33%, unknown 14%. Pt characteristics in the lenalidomide arm and placebo arm respectively were: median age (range) 58 (29-70) and 57 (39-70); male gender 48% and 52%; β2M >2.5 mg/L, 28% and 27%. For 554 pts with complete data, induction regimens were thalidomide based (27%), lenalidomide based (22%), bortezomib based (20%), bortezomib and thalidomide based (12%), bortezomib and lenalidomide based (9%), dexamethasone based (4%), lenalidomide and thalidomide (3%), lenalidomide, thalidomide and bortezomib (1%), other (1%) and missing (1%); hence 74% of pts received either lenalidomide or thalidomide prior to enrollment. The primary endpoint of the study, TTP was met in a planned protocol interim analysis in the 3rd quarter of 2009 and the study results were released on 12/17/09. This updated 3rd interim analysis for TTP includes further events up until 12/17/09 after which study pts were un-blinded. This interim analysis is based on 460 randomized pts with approximately 33% of the required number of events (progression or death before progression) observed. The median follow-up is 17.5 months from ASHCT. The number of events among 231 pts randomized to lenalidomide was 44 compared to 91 among 229 pts randomized to placebo. The one-sided unadjusted P-value was <0.0001. Pts receiving lenalidomide experienced a 61% reduction in the risk of disease progression or death when compared to pts receiving placebo. The estimated hazard ratio was 0.39 (95% CI,0.27-0.56 p < 0.0001). The preliminary estimated median TTP is 42.3 months for the lenalidomide arm and the estimated median TTP is 21.8 months for the placebo arm. Deaths in the lenalidomide and placebo arms were 19 and 28 respectively (p=0.13) and as of this analysis, there is no difference between these two arms. Significant improvements in TTP were observed in the lenalidomide maintenance arm regardless of β2M level or prior thalidomide or lenalidomide induction therapy. For 389 reported pts, the post-randomization, hematologic AEs were Gr 3 (32%), Gr 4 (13%) and Gr 5 (0) for the lenalidomide arm and Gr 3 (6%) Gr 4 (4%) and Gr 5 (0) for placebo (p=0.0001). The non-hematologic AEs were Gr 3 (30%), Gr 4 (3%) and Gr 5 (1%) for the lenalidomide arm and Gr 3 (19%), Gr 4 (3%), and Gr 5 (2%) for placebo (p=0.0048). Comparing lenalidomide versus placebo post-randomization pooled Gr 3–5 AEs, there were significantly more episodes of thrombocytopenia (11% versus 3%, p=0.01), neutropenia (44% vs 8%, p<0.0001) anemia (5% vs 1%, p=0.0082) and all infections (16% vs 3%, p<0.0001) with lenalidomide. There were no significant differences in incidence of fatigue, neuropathy, rash and thromboembolism. A minority of patients discontinued therapy due to AEs (12%, 28 of 231 on lenalidomide vs 2%, 5 of 229 on placebo) and for other reasons (13%, 29 of 231 on lenalidomide vs 6%, 14 of 231 on placebo).
Long term administration of lenalidomide is feasible. When compared to placebo controls, lenalidomide initiated at day 100–110 post-AHSCT in multiple myeloma patients significantly delays TTP.
McCarthy:Celgene: Honoraria, Research Funding. Off Label Use: Lenalidomide maintenance therapy for myeloma following autologous hematopoietic cell transplant. Anderson:Millenium: Consultancy, Honoraria; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Merck: Consultancy; Bristol Myers Squibb: Consultancy; Acetylon: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Hurd:Celgene: Research Funding. Giralt:Celgene: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau. Stadtmauer:Celgene: Speakers Bureau. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Vij:Celgene: Honoraria, Speakers Bureau. Callander:Millenium: Research Funding. Maziarz:Millenium: Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Landau:Millenium: Membership on an entity's Board of Directors or advisory committees. Martin:Celgene: Speakers Bureau; Millenium: Speakers Bureau; Novartis: Speakers Bureau. Qazilbash:Celgene: Speakers Bureau. Shea:Millenium: Consultancy, Research Funding.
Background CEA is expressed in >90% of pancreatic cancers (PC) and may be an appropriate immunotherapy target. CEA is poorly immunogenic due to immune tolerance; CAP1-6D, an altered peptide ligand ...can help bypass tolerance. We conducted a pilot randomized phase I trial in PC patients to determine the peptide dose required to induce an optimal CD8.sup.+ T cell response. Methods Patients with a PS 0-1, HLA-A2+ and CEA-expressing, previously-treated PC were randomized to receive 10 mug (arm A), 100 mug (arm B) or 1000 mug (arm C) of CEA peptide emulsified in Montanide and GM-CSF, given every 2 weeks until disease progression. Results Sixty-six patients were screened and 19 enrolled of whom 14 received at least 3 doses of the vaccine and thus evaluated for the primary immunologic endpoint. A median of 4 cycles (range 1-81) was delivered. Median and mean peak IFN-gamma T cell response by ELISPOT (spots per 10.sup.4 CD8.sup.+ cells, Arm A/B/C) was 11/52/271 (A vs. C, p = 0.028) for medians and 37/148/248 (A vs. C, p = 0.032) for means. T cell responses developed or increased in 20%/60%/100% of pts in Arms A/B/C. Seven of the 19 patients remain alive at a minimum 32 months from trial initiation, including three with unresectable disease. Conclusions The T cell response in this randomized phase I trial was dose-dependent with the 1 mg CEA peptide dose eliciting the most robust T cell responses. A signal of clinical benefit was observed and no significant toxicity was noted. Further evaluation of 1 mg CEA peptide with stronger adjuvants, and/or combined with agents to overcome immune inhibitory pathways, may be warranted in PC pts. Trial registration ClinicalTrials.gov NCT00203892 Keywords: Pancreatic Cancer, Vaccine, Immunization, CEA
Abstract Granulocyte colony-stimulating factor (G-CSF) has been reported to exacerbate vaso-occlusive crises in sickle cell disease. It has been recommended to avoid its use for stem cell ...mobilization in this population, yet autologous transplant is the standard of care and at times a life-saving treatment for patients with various hematologic malignancies such as relapsed aggressive lymphoma or multiple myeloma. We report 5 cases of patients with sickle cell disease and related hemoglobinopathies who underwent granulocyte-colony stimulating factor (G-CSF)-mobilization of peripheral blood stem cells (PBSC). Three of them developed manageable vaso-occlusive pain symptoms requiring parenteral narcotics alone. The 2 others had no complications. These cases demonstrate that stem cell mobilization using G-CSF, although complicated and not without risk, is feasible in patients with sickle cell syndromes.
PDF
