Phase 1 trial of autologous dendritic cell vaccination with imiquimod immunomodulation in children and adults with refractory sarcoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11542-11542
Author(s):  
Aditi Dhir ◽  
Tulay Koru-Sengul ◽  
James Grosso ◽  
Gina Z. D'Amato ◽  
Matteo M. Trucco ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Disease Progression ◽  
Surgical Resection ◽  
Dose Level ◽  
Dose Escalation ◽  
Phase 1 ◽  
Autologous Dendritic Cell ◽  
Dc Vaccine ◽  
Disease Free

11542 Background: Sarcomas are rare, heterogeneous, and aggressive neoplasms that often affect otherwise healthy individuals. Patients with advanced or metastatic sarcomas have dismal outcomes. Immunotherapy presents promising new modalities to help treat sarcomas. One such therapy, autologous dendritic cell (DC) vaccines, using antigen-loaded DCs, intensify the adaptive immune response by enhancing T-cell activity and inducing tumor cell death through apoptosis and cytolysis. We present the results of a phase 1 study of DC vaccine for refractory sarcomas. Methods: A phase 1 dose-escalation study of autologous DC vaccination was conducted in children and adults with recurrent/refractory sarcomas who underwent surgical resection of a primary or metastatic tumor between 2014-2019. A 5+3 dose-escalation schema was chosen to determine safety and recommended phase 2 dose. Patient monocytes were collected by pheresis and incubated with GM-CSF plus IL-4 to generate immature DCs which were then loaded with autologous tumor lysates from the patient’s surgical resection. Three dose levels, 3, 6, and 12 million DCs per treatment were tested. The DC product was administered intradermally in imiquimod-treated skin to complete in situ maturation. Treatment consisted of four weekly injections of the DC product, followed by four monthly “boosters” of tumor lysate. The primary and secondary endpoints included safety/feasibility and preliminary clinical efficacy, respectively. Results: Nineteen patients were enrolled with a median age 50 years (13-75 years) and 47% female. Seven patients were treated on dose level 1 and six each on dose level 2 and 3. Thirteen patients received all planned injections while the remaining six patients progressed during treatment. There was no treatment related dose limiting toxicity. Grade 1-2 fever, headache, arthralgia, injection site reaction attributable to treatment were noted in four patients. There were no adverse events > grade 2. Disease progression before or after completion of study treatment was noted in 15 patients with a median PFS of 9.5 months (95%CI 5.6-28.7). The two-year PFS and OS was 36.8% and 68.1%, respectively. There were seven deaths due to disease, one patient was discharged to hospice and two patients have been lost to follow up. Five patients are currently receiving alternative therapy. Four patients remain in follow up without evidence of disease progression including three patients (pleomorphic myxofibrosarcoma, pleomorphic myosarcoma, and leiomyosarcoma) who are disease free over two years from initiating study therapy and one pediatric patient (Ewing sarcoma) disease free for over one year. Conclusions: Autologous DC vaccine with imiquimod immunomodulation for patients with relapsed/refractory sarcomas is feasible and well-tolerated. Refinement to augment initial and sustained antitumor activity is needed. Clinical trial information: NCT01803152.

Safety of nivolumab in combination with dendritic cell vaccines in recurrent high-grade glioma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13526-e13526
Author(s):  
Katherine B. Peters ◽  
Gerald E. Archer ◽  
Pamela Norberg ◽  
Weihua Xie ◽  
Stevie Threatt ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Surgical Resection ◽  
Phase 1 ◽  
Randomized Study ◽  
High Grade Glioma ◽  
Checkpoint Blockade ◽  
Phase Iii ◽  
High Grade ◽  
Who Grade ◽  
Dc Vaccine

e13526 Background: Recurrence of high-grade glioma (HGG) (WHO grade III-IV) is a nearly universal phenomenon and necessitates the development of new therapeutic modalities. Two possible immunotherapeutic modalities are checkpoint blockade with agents such as nivolumab, a blocking antibody against the inhibitory checkpoint programmed cell death-1 (PD-1), and dendritic cell (DC) vaccination. We have shown in phase 1 and 2 trials that DC vaccination against the glioblastoma (GBM)-associated antigen human cytomegalovirus pp65-lysosomal-associated membrane protein (CMVpp65) is safe and possesses potential benefit. We hypothesized that nivolumab-induced immune checkpoint blockade could enhance efficacy of DC vaccination. Therefore, we undertook a phase 1 study to evaluate safety of nivolumab in combination with CMVpp65 mRNA pulsed DC vaccination in subjects with first or second recurrence of resectable HGG. Methods: We performed a phase 1, single-center, randomized study of nivolumab alone versus nivolumab + DC vaccination prior to planned surgical resection for both groups. We administered nivolumab 3 mg/kg IV q2weeks for 8 weeks followed by surgery and planned continuation of nivolumab. For the group receiving nivolumab + DC vaccination, we administered 3 vaccines before surgical resection with both groups receiving 5 planned post-resection DC vaccines. Primary endpoint was safety assessment using NCI-CTCAE 4.03. Results: We enrolled 6 subjects (4: GBM, 1: anaplastic astrocytoma, 1: anaplastic oligodendroglioma) with 3 receiving nivolumab alone and 3 receiving nivolumab + DC vaccination. Age range was 45-63 years subjects. We documented similar adverse events in both groups with most common grade 1-2 toxicities being fatigue (2 subjects, nivolumab alone) and thrombocytopenia (2 subjects, nivolumab + DC vaccine). Grade 4 toxicities included wound infection (2 subjects, nivolumab + DC vaccine) and meningitis (1 subject, nivolumab + DC vaccine). While we designed the study to enroll 66 subjects, we terminated the study early in light of CheckMate 143 phase III data showing nivolumab did not improve overall survival in recurrent GBM. Conclusions: Safety of nivolumab + DC vaccination in recurrent HGG is similar to nivolumab alone. Continued evaluation of new therapeutics including immunotherapy is underway for this patient population. Clinical trial information: NCT02529072.

scholarly journals Combination Trial of Duvelisib (IPI-145) with Bendamustine, Rituximab, or Bendamustine/Rituximab in Patients with Lymphoma or Chronic Lymphocytic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3928-3928 ◽  
Author(s):  
Ian W. Flinn ◽  
Mohamad Cherry ◽  
Michael Maris ◽  
Jeffrey V. Matous ◽  
Jesus G. Berdeja ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Expansion Phase ◽  
Time Plot

Abstract Background: Duvelisib, a potent inhibitor of the δ and γ isoforms of phosphoinositide-3-kinase (PI3K) is being developed as a potential therapeutic in hematologic malignancies including chronic lymphocytic leukemia (CLL), as well as B and T cell lymphoma. Single agent bendamustine (B), rituximab (R), and their combination have demonstrated proven activity in iNHL and CLL. Combining duvelisib with bendamustine or rituximab alone or with both drugs may improve response rates and the durability of remission. The primary objective of this trial is to characterize the safety, maximum tolerated dose (MTD), and a preliminary efficacy profile of duvelisib given in combination with rituximab (Arm 1-DR), bendamustine plus rituximab (Arm 2-DBR) or bendamustine (Arm 3-DB) in subjects with select relapsed/refractory lymphoma or CLL. Methods: Pts with relapsed CLL or NHL, ECOG performance status (PS) ≤2, and adequate organ function were enrolled. The subject population during dose escalation was limited to relapsed NHL. During the dose expansion phase, each treatment arm enrolled to population specific cohorts to continue to assess efficacy. Arm 1 (DR) received rituximab 375 mg/m2 IV weekly for 2, 28 day cycles plus duvelisib PO BID until disease progression or intolerance. Arm 2 (DBR)received rituximab 375 mg/m2 IV weekly for 2, 28 day cycles, bendamustine 90 mg/m2 IV for NHL pts or 70 mg/m2 IV for CLL pts on Days 1 and 2 of the first six cycles plus duvelisib PO BID until disease progression or intolerance. Arm 3 (DB) received bendamustine 120 mg/m2 IV on Days 1 and 2 of the first six cycles plus duvelisib PO BID up to 12 cycles. Three different dose levels of duvelisib, 25, 50, and 75 mg PO BID were initially explored. Pts were evaluated for response every 3 cycles according to specific criteria for their disease. Results: Between August 2013 and April 2015, 48 pts, median age 67 yrs (40-83) were enrolled; 12 NHL pts in the dose escalation portion and 36 pts (18 CLL, 18 NHL) in dose expansion. Pts had a median of 2 prior therapies (1-7). In arms 1 (DR) and 2 (DBR), no dose limiting toxicities were seen at the highest dose level of duvelisib (75 mg bid). In arm 3 (DB), with a higher dose of bendamustine, 1 pt developed a DLT at the 50 mg BID dose level of duvelisib (febrile neutropenia, neutropenia ≥ 7 days, thrombocytopenia ≥ 7 days, and liver toxicities which resulted in a treatment delay of ≥ 7 days). The MTD was not reached in this study but given recent data of single agent duvelisib showing no advantage in doses >25 mg BID, pts on the expansion phase were treated with 25mg BID. The AE profile of the drug combination is consistent with toxicities of the single agents (Table 1). There have been 2 potentially treatment-related deaths (cardiac arrest in a pt with history of hypertension and diabetes, and pneumonia), both on Arm 1. 38 pts were evaluable for response with an ORR of 74% (8% CR, 66% PR, 16% SD and 10% PD). The ORR of NHL and CLL pts were 64% and 92% respectively. With a median follow up of 16.25 mos, median progression free survival is 13.7 mos overall. Median overall survival (OS) has not been reached, but 15 mo OS probability is 82%. Pharmacokinetics analysis is consistent with the monotherapy Phase I trial of duvelisib (Figure 2) and is not effected by bendamustine. Conclusions: Analysis of duvelisib administered in combination with bendamustine and rituximab shows these combinations to be generally well-tolerated with encouraging response. Further follow-up is required to better characterize both response rates and durability of remissions. Table 1. Treatment-related AEs (≥15% all pts) ARM 1 (N=28) ARM 2 (N=18) ARM 3 (N=2) Preferred Term G 1/2 G 3/4 G 1/2 G 3/4 G 1/2 G 3/4 Treated (N=48) RASH 8 (29%) 3 (11%) 3 (17%) 3 (17%) 0 17 (35%) DIARRHEA 8 (29%) 3 (11%) 2 (11%) 1 (6%) 1 (50%) 0 15 (31%) FATIGUE 9 32%) 0 4 (22%) 1 (6%) 1 (50%) 0 15 (31%) NAUSEA 5 (18%) 0 4 (22%) 0 1 (50%) 0 10 (21%) ALANINE AMINOTRANSFERASE INCREASED 5 (18%) 1 (4%) 3 (17%) 0 0 0 9 (19%) NEUTROPENIA 1 (4%) 5 (18%) 0 3 (17%) 0 0 9 (19%) ASPARTATE AMINOTRANSFERASE INCREASED 4 (14%) 1 (4%) 3 (17%) 0 0 0 8 (17%) ANAEMIA 3 (11%) 1 (4%) 2 (11%) 0 1 (50%) 0 7 (15%) PRURITUS 3 (11%) 0 3 (17%) 0 0 0 6 (13%) UPPER RESPIRATORY TRACT INFECTION 5 (18%) 0 1 (6%) 0 0 0 6 (13%) CONSTIPATION 4 (14%) 0 1 (6%) 0 0 0 5 (10%) MUCOSAL INFLAMMATION 3 (11%) 1 (4%) 1 (6%) 0 0 0 5 (10%) Figure 1. Mean IPI-145 Concentration vs Time Plot with Tx Arms Overlaid for the First 6 Hours (Linear) Figure 1. Mean IPI-145 Concentration vs Time Plot with Tx Arms Overlaid for the First 6 Hours (Linear) Disclosures Flinn: Celgene Corporation: Research Funding. Berdeja:Curis: Research Funding; Abbvie: Research Funding; Janssen: Research Funding; Array: Research Funding; Acetylon: Research Funding; Takeda: Research Funding; Celgene: Research Funding; BMS: Research Funding; Onyx: Research Funding; MEI: Research Funding; Novartis: Research Funding.

Preliminary results of a phase I clinical trial using an autologous dendritic cell cancer vaccine targeting HER2 in patients with metastatic cancer or operated high-risk bladder cancer (NCT01730118).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2639-2639
Author(s):  
Hoyoung M. Maeng ◽  
Lauren Virginia Wood ◽  
Brittni Moore ◽  
Mohammadhadi H. Bagheri ◽  
Santhana Webb ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Bladder Cancer ◽  
Dendritic Cell ◽  
High Risk ◽  
Phase I ◽  
Dose Level ◽  
Cardiac Toxicity ◽  
Metastatic Cancer ◽  
Autologous Dendritic Cell ◽  
Dc Vaccine

2639 Background: We developed a HER2 targeting autologous dendritic cell (DC) vaccine transduced with an adenovirus expressing the extracellular and transmembrane domains of HER2 (AdHER2). In mice, the homologous vaccine cured virtually all mice with established or metastatic tumors. Protection was dependent on antibodies against HER2 that inhibited phosphorylation, but was ADCC independent. We translated these findings into a clinical trial. Methods: This is an open-label, phase I study in patients with 1) metastatic cancer that progressed after ≥ 1 standard therapies, or 2) history of high risk bladder cancer with definitive treatment, whose tumor is HER2 immunohistochemistry (IHC) score ≥ 1+ or FISH HER2/CEP17 ratio ≥ 1.8. Part 1 of the study enrolled patients naïve to HER2-directed therapies and Part 2 enrolled patients who progressed with ≥ 1 anti-HER2 therapy. Results: In Part 1, the lowest dose level (5E+6 viable DCs, N=7, 2 inevaluable) showed no benefit. At the second and third dose level (10E+6 and 20E+6; N=7 and N=4; 0 and 1 inevaluable in each), 1 CR (ovarian), 1 PR (stomach), and 3 SD (1 ovarian carcinosarcoma and 2 colon) were observed. Two bladder cancer patients who received vaccine as an adjuvant did not recur for +24 and +36 month each. In Part 2 (N=6, 2 inevaluable), 1 male breast cancer patient showed SD. Response assessed by Modified Immune Related Response Criteria is summarized in the Table. Injection-site reactions occurred in all patients and were self-limited. Echo, EKG and troponin follow up to 2 years showed no cardiac toxicity. Dose-expansion cohort (40E+6) is enrolling. Conclusions: We have translated a cancer vaccine from mice to a clinical trial. Preliminary results of a phase I trial of an autologous AdHER2 DC vaccine show potential clinical benefit in select patients with HER2 expressing tumors with no cardiac toxicity. Clinical trial information: NCT01730118. [Table: see text]

A first-in-human, multicenter, open-label, phase 1 study of ATOR-1017, a 4-1BB antibody, in patients with advanced solid malignancies.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2646-2646
Author(s):  
Gustav J. Ullenhag ◽  
Jeffrey Yachnin ◽  
Ana Carneiro ◽  
Emma Elison ◽  
Malin Carlsson ◽  
...  
Keyword(s):  
Disease Progression ◽  
Dose Level ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Choroidal Melanoma ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Phase 1 Study ◽  
Solid Malignancies

2646 Background: ATOR-1017 is a human agonistic IgG4 antibody targeting the co-stimulatory receptor 4-1BB (CD137). It is developed to activate T cells and natural killer cells in the tumor environment, leading to immune-mediated tumor cell killing. This is a first-in-human, multicenter, phase 1 study (NCT04144842). Methods: In this study, ATOR-1017 is administered intravenously every 21 days as a single agent to patients with solid malignancies. ATOR-1017 is administered until confirmed progressive disease, unacceptable toxicity or withdrawal of consent. The primary objective of the study is to determine the maximum tolerated dose, assessed by adverse events (AEs) and dose limiting toxicities (DLTs), and the recommended phase 2 dose. Secondary objectives include pharmacokinetics, immunogenicity and clinical efficacy, assessed with CT scans using response criteria for use in studies testing immunotherapeutics (iRECIST). The study uses a single cohort design for doses up to 40 mg, and thereafter a modified 3+3 design. Results: The first patient was dosed in December 2019; by 22 Jan 2021, twelve patients have been exposed to ATOR-1017. The following dose levels have been evaluated; 0.38 mg; 1.5 mg; 5 mg; 15 mg; 40 mg and 100 mg. Dose escalation is ongoing, and the 200 mg dose level is under evaluation. The maximum tolerated dose has not been reached. The following cancer types are included; ovarian cancer (n = 1), choroidal melanoma (n = 3), anal cancer (n = 1), cholangiocarcinoma (n = 1), gastrointestinal stromal tumor (n = 1), breast cancer (n = 1), pancreatic cancer (n = 1), adenoid cystic cancer (n = 1), malignant melanoma (n = 1), colorectal cancer (n = 1). Drug-related AEs were reported in 5 out of 12 patients; one patient experienced a grade 3, all others were grade 1 or 2. There have been two episodes each of chest pain (grades 2 and 3) and headache (grades 1 and 2). Single cases of pyrexia, upper abdominal pain, mouth ulceration, nausea, leukopenia, neutropenia, cytokine release syndrome (CRS), arthralgia, neck pain, and rash were also reported. No DLTs have been observed in the study to date. The median age of the patients were 48.5 years (range 34-76). Patients received a median of 2 prior lines of therapy (range 1-4). The median time on study were 15 weeks (range 0.14-51). Six patients are on study, and six patients have discontinued treatment. Reasons for discontinuation include; investigator decision (n = 1), confirmed disease progression (n = 1), withdrawal of consent (n = 1), death due to disease progression (n = 1) and other reason (n = 2). Preliminary PK data show dose-proportional kinetics up to 100 mg. Best response has been stable disease. Conclusions: ATOR-1017 is safe and well-tolerated up to 100 mg. Dose escalation continues and the current dose level is 200 mg. Clinical trial information: NCT04144842.

scholarly journals ACTR-63. PHASE I DOSE ESCALATION STUDY OF PROCASPASE ACTIVATING COMPOUND-1 (PAC-1) IN COMBINATION WITH TEMOZOLOMIDE IN PATIENTS WITH RECURRENT ANAPLASTIC ASTROCYTOMA OR GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi28-vi28
Author(s):  
Matthias Holdhoff ◽  
Martin Nicholas ◽  
Richard Peterson ◽  
Oana Danciu ◽  
Stefania Maraka ◽  
...  
Keyword(s):  
Dose Level ◽  
Dose Escalation ◽  
Anaplastic Astrocytoma ◽  
Caspase 3 ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Data ◽  
Dose Escalation Study ◽  
Level 1 ◽  
Level 2

Abstract BACKGROUND Procaspase activating compound -1 (PAC-1) is a small molecule that catalyzes conversion of procaspase-3 to caspase-3 which induces apoptosis in cancer cells. Glioblastoma (GBM) is among the tumors with high concentrations of procaspase-3 and low levels of caspase-3. PAC-1 crosses the blood brain barrier and has been shown to synergize with temozolomide (TMZ) in canine malignant glioma and meningioma that arise spontaneously. METHODS This is a multicenter phase 1 dose-escalation study to assess the maximum tolerated dose (MTD) of PAC-1 administered days 1–21 in combination with TMZ days 8–12 at a dose of 150 mg/m2 of each 28 day cycle in subjects with recurrent anaplastic astrocytoma (AA) or GBM. A modified Fibonacci 3 + 3 design is used with up to 4 dose levels of PAC-1 (375, 500, 625 and 750 mg/day). Neurologic toxicity, including cognitive function, is closely monitored throughout the trial. INTERIM DATA: A total of 14 subjects have been enrolled to-date. Of these, 7 at dose level 1, PAC-1 375 mg/day (6 GBM, 1 AA; median age 58y, range 25–75) and 7 at dose level 2, PAC-1 500 mg/day (5 GBM, 2 AA; median age 51y, range 35–60). Best responses to-date were 2 subjects with a partial response and 2 with stable disease. Grade 3 (hepatotoxicity) and 4 (cerebral edema) was reported as possibly related to PAC-1 in 1 patient at dose level 1. The median number of cycles received was 4 (range, 1–12+) at dose level 1 and 2 (range, 1–3) at dose level 2. Enrollment to dose level 2 has been completed and data analysis is ongoing. Updated response and toxicity as well as pharmacokinetic data will be presented.

A Phase I-II Dose Escalation Trial of Clofarabine Plus Melphalan and Thiotepa Followed by Unmodified Allogeneic Stem Cell Transplant (SCT) for the Treatment of High Risk or Advanced Acute Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2354-2354
Author(s):  
Farid Boulad ◽  
Nancy A Kernan ◽  
Susan E Prockop ◽  
Andromachi Scaradavou ◽  
Trudy N Small ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Phase I ◽  
Dose Level ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Acute Leukemias ◽  
Unrelated Donors ◽  
Disease Free

Abstract Abstract 2354 High-risk or advanced acute leukemias are associated with poor outcome even with the use of stem cell transplantation (SCT) with or without total body irradiation (TBI). Based on encouraging results with the use of clofarabine (CLO) for reinduction treatment of acute leukemias, we have developed a phase I/II protocol using this agent with melphalan (Mel) and thiotepa (Thio) followed by unmodified SCT for the treatment of patients (pts) with high-risk (HR) leukemias. To date, 28 consecutive pts were treated on, or as per protocol, with 26 pts evaluable for follow-up. There were 15 males and 11 females aged 1–58 years (median 5.3 years). Cytoreduction consisted of CLO at dose level I of 20 mg/m2/day × 5 days (n=23) or at dose level II of 30 mg/m2/day × 5 (n=3), Thio 10 mg/Kg/day × 1 day and Mel 70 mg/m2/day × 2 days. Graft-versus-host disease (GvHD) prophylaxis consisted of tacrolimus and mycophenolate mofetil (MMF), or tacrolimus and methotrexate. Twenty pts had acute lymphoblastic leukemia (ALL) in complete remission (CR1; n=5), CR2 (n=5), CR3 (n=9), or relapse (n=1). Five pts had acute myeloid leukemia (AML), in CR1 (n=1), CR2 (n=2), or CR3 (n=2). One pt had myelodysplastic syndrome (MDS) in RAEB. For the pts with ALL in CR1, very HR features included: Infant MLL (N=2), Philadelphia (Ph1) chromosome (N=2) and Induction failure (N=1). For the pts with ALL in CR2, HR features included: Infant MLL (N=1), 2nd SCT (N=1), Ph1 and 2nd SCT (N=2), while 1 pt had prior CNS infarcts precluding the use of TBI. The one pt with AML in CR1 had M7-AML. This was a first SCT for 14 pts, a 2nd SCT for 11 pts and 3rd SCT for 1 pt, with time from previous SCT to the present one being 5–73 months (median 11.3 mo) for those 12 pts. Donors were HLA-matched siblings (n=8), HLA matched unrelated donors (n=8), or HLA mismatched unrelated donors (N=10). Stem cell grafts were bone marrow (n=12), peripheral blood (n=7) or double cord blood (n=7) stem cells. Twenty four of the 26 evaluable pts engrafted, while 2 pts died prior to engraftment. Toxicity of the SCT cytoreduction included elevation of hepatic transaminases in 17 of 26 evaluable pts (AST elevation of 5–19 fold and ALT elevation of 7–16 fold), with a subsequent normalization in all pts. Mucositis was mostly at acceptable grade 1–2 levels. Two pts developed a syndrome of renal and hepatic insufficiency leading to hepatic veno-occlusive disease (VOD) (1 pt at each of the 2 dose levels). Non-relapse mortality included: VOD (N=2), infections (N=3), treatment related sarcoma, a malignancy secondary to the irradiation received with a prior transplant (N=1). With a follow-up of 3–57 mos (median 21 mos), 15 of the 26 pts are alive, disease-free. Five pts relapsed and 4 died subsequently of disease, while 6 pts died of non-relapse morality. Overall (OS) and disease-free survival (DFS) at 2 years were both 58%. DFS was 56% for pts > 18 years and 53% for pts < 18 years (p =0.36); it was 64% for recipients of a first HSCT and 41% (p=0.97) for recipients of a second or third HSCT. Five pts (4 recipients of unrelated donor SCT; 3 from mismatched donors) developed Grade 2–4 acute GvHD. Four of these pts went on to develop chronic GvHD. Immune reconstitution was rapid; for the evaluable pts, it included absolute CD4 counts > 200 cells/L at 1–3 mos for 15 pts and at 4–8 mos for 4 pts. This cytoreductive regimen represents a promising approach for the transplantation of patients with high risk acute leukemias. It was well tolerated for pts requiring a second SCT and is also associated with rapid immune recovery. Ultimately, a large scale study would need to be done to determine if this approach could offer equal or superior results to TBI containing regimens for ALL or AML. Disclosures: No relevant conflicts of interest to declare.

Potent Stem Cell Mobilization with the Novel CXCR4 Antagonist POL6326 - Results of a Phase IIa Dose Escalation Study in Comparison to G-CSF

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 511-511 ◽  
Author(s):  
Darja Karpova ◽  
Susanne Brauninger ◽  
Eliza Wiercinska ◽  
Ariane Kraemer ◽  
Belinda Stock ◽  
...  
Keyword(s):  
Stem Cell ◽  
Healthy Volunteer ◽  
Dose Level ◽  
Dose Escalation ◽  
The Novel ◽  
Cxcr4 Antagonist ◽  
Cd34 Cells ◽  
Cell Mobilization ◽  
Over Time

Abstract Background: Stem cell mobilization (SCM) with G-CSF is efficient but - although overall safe - inconvenient because of the five-day injection regime and certain contraindications. Side effects, sometimes severe, are frequent. These disadvantages fuel the quest for alternative mobilizing agents. Mobilization with the CXCR4-inhibitor plerixafor is rapid, albeit insufficiently efficacious on its own. POL6326, a potent 2nd generation macrocycle CXCR4 antagonist, has demonstrated rapid mobilization kinetics and efficacy in mice. We herein report the results of a Phase IIa dose escalation trial where SCM in response to POL6326 was compared with G-CSF in healthy volunteer stem cell donors. Methods: In this Phase IIa open label trial, healthy volunteer stem cell donors with average mobilization (121±7 CD34+ cells/μL, MW±SEM)after a five-day course of G-CSF, and a wash-out period of at least 6 weeks, received POL6326 at 500-2500 µg/kg as a single 2-hour i.v. infusion. Safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) were assessed in 3-10 subjects/dose group. Subgroups received two doses of POL6326, 1000 and 2500 µg/kg or 1500 and 2500 µg/kg, at least 2 weeks apart (paired intra-individual analysis). For PK and PD blood samples were collected before (0) and at 2, 3, 4, 6, 8 and 24 hrs after infusion start. Complete blood count, CD34+, CFU-C count and PK were assessed at all time points. At 0, 4, 8 and 24 hrs extensive phenotyping of mobilized mature and immature leukocyte subsets was performed. Eight to 14 days after treatment volunteers underwent extensive clinical and laboratory follow-up. Results: POL6326 was very well tolerated. Several volunteers experienced a mild urticarial or itchy macular rash which responded well to H1/H2 blockade. Rating of tolerability/adverse events by volunteers (questionnaire) compared favourably with G-CSF administration. Exposure (Cmax, AUC) was dose-linear. At all doses tested POL6326 mobilized CD34+ progenitor cells and colony-forming cells (CFU-C, Figure 1) exceeding reported peak mobilization with plerixafor in donors at all except the lowest dose levels. In this dataset mobilization after doses of 2000 or 2500 µg/kg did not appear meaningfully stronger than after 1500 µg/kg. The SCM response for CD34+ cells to doses ≥1500 µg/kg was 36.9±2.4/µL (mean±SEM), or 1/3 that of G-CSF (y=0.324x). Good SCM with G-CSF was predictive of good SCM with POL6326 (r=0.63). One/5.7 POL6326-mobilized CD34+ cells was clonogenic (G-CSF: 1 CFU-C/3.4 CD34+ cells) possibly indicating a more immature phenotype of CD34+ cells mobilized by POL6326. POL6326 caused mixed leucocytosis with peak values in the mid-20K/µL. B-lymphocytosis was more and neutrophilia and monocytosis were less pronounced after POL6326 than G-CSF. Compared to G-CSF the subset of plasmocytoid dendritic cell progenitors (pDC) was enriched to a distinct population within the CD34+ cells following SCM with POL6326 as previously described for plerixafor. At the 24 h time point, blood values were well on their way towards normal, and at follow-up all laboratory values had normalized. Summary/Conclusions: The novel CXCR4-antagonist POL6326 is safe, well tolerated, and provides efficient mobilization of HSPCs. Based on the number of mobilized CD34+ cells at higher doses in this study, we conclude that a standard dose of 4x10E6 CD34+ cells/kg can be extracted with a single apheresis for most recipients unless their body weight significantly exceeds the donor weight. However, exploration of alternative dosing regimens may provide even higher mobilization responses. POL6326 can be an effective mobilizing agent for allogeneic donors, including subjects with contra-indications to G-CSF. Figure 1. Mobilization of CD34+ cells (left) and CFU-C (right) over time is shown (mean±SEM for each dose level of POL6326). Figure 1. Mobilization of CD34+ cells (left) and CFU-C (right) over time is shown (mean±SEM for each dose level of POL6326). Figure 2. Figure 2. Disclosures Escot: Polyphor Ltd.: Employment. Douglas:Polyphor Ltd.: Employment. Romagnoli:Polyphor Ltd.: Employment. Chevalier:Polyphor Ltd.: Employment. Dembowsky:Polyphor Ltd.: Consultancy. Hooftman:Polyphor Ltd.: Employment. Bonig:Polyphor Ltd.: Research Funding.

A phase 1B study of a MUC1 pulsed autologous dendritic cell (DC) vaccine as adjuvant therapy in patients (Pts) with resected pancreatic or biliary tumors

2004 ◽  
Vol 22 (14_suppl) ◽  
pp. 2578-2578 ◽  
Author(s):  
O. J. Finn ◽  
T. Whiteside ◽  
J. McKolanis ◽  
A. J. Moser ◽  
H. Zeh ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Adjuvant Therapy ◽  
Autologous Dendritic Cell ◽  
Dc Vaccine ◽  
Phase 1B

Comparison of long-term outcome between endoscopic submucosal dissection and surgical resection for early gastric cancer.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 144-144
Author(s):  
Boo Gyeong Kim ◽  
Byung-Wook Kim ◽  
Joon Sung Kim ◽  
Sung Min Park ◽  
Keun Joon Lim ◽  
...  
Keyword(s):  
Overall Survival ◽  
Survival Rate ◽  
Surgical Resection ◽  
Disease Free Survival ◽  
Overall Survival Rate ◽  
Free Survival ◽  
Resection Group ◽  
Disease Free

144 Background: The aim of this study is to evaluate the long-term clinical and oncologic outcome of ESD for differentiated EGC of an expanded indication compared to surgical resection. Methods: Retrospective analyses were performed in patients who underwent ESD or surgical resection for EGC of an expanded indication from 2006 and 2008 in Incheon St. Mary’s Hospital, Seoul St. Mary’s Hospital, Yeouido St. Mary’s Hospital, and St. Paul’s Hospital. First arm study was performed according to pre-ESD diagnosis including pathologic diagnosis and endoscopic findings. Second arm study was obtained from post-ESD final pathologic result. All the patients were checked with endoscopy and stomach CT regularly at least 5 years. Clinical outcomes, disease free survival and overall survival were compared between the ESD group and surgical resection group in each arm. Results: In first arm study, 41 patients who received ESD and 106 patients who received surgical resection were enrolled. Metachronous recur was found in 4 patients among ESD group and in 2 patients among surgical resection group during the follow up period. There was no local recurrence in both groups. The disease free survival was not different between the two groups (ESD vs surgical resection; 87.8 vs 95.3%, p=0.291). The 5-year overall survival rate was 100% in both groups. In second arm study, 74 patients who received ESD and 165 patients who received surgical resection were enrolled. Metachronous recur was found in 5 patients among ESD group and in 2 patients among surgical resection group during the follow up period. Local recurrence did not occur in both groups. Surgical resection group was superior to ESD group in disease free survival (97.6% vs 87.6%, p=0.002). The 5-year overall survival rate was 100% in both groups. Conclusions: ESD for EGC might be acceptable considering the overall survival rates. However, intensive surveillance should be performed to find the metachronous recur after ESD.

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