79P Immune-related adverse events are correlated with significantly improved outcome in a phase I trial population exposed to combination immunotherapy

Abstract Abstract 2894 Antibody (Ab) therapies such as the CD20 monoclonal abs rituximab and ofatumumab are commonly used in CLL alone and in combination with chemotherapy, however, CD20 density is low on CLL cells, suggesting this may not be the ideal target. CD19, which is ubiquitously expressed on CLL cells and those of other B cell malignancies is a reasonable candidate for ab targeting. XmAb5574 is a novel humanized IgG1 CD19 monoclonal ab with an engineered Fc region to enhance Fc gamma receptor binding affinity. In vitro, this ab demonstrates direct cytotoxicity and antibody dependent cellular phagocytosis similar to rituximab, however, shows enhanced natural killer antibody dependent cellular cytotoxicity compared to other therapeutic abs used in CLL (Awan, FT Blood 2009). We have performed a first in human trial of this ab as a single agent in relapsed or refractory (R/R) CLL, and present the results in this report. This study is a multi-institutional phase I trial of XmAb5574 in patients (pts) with R/R CLL. Eligible pts were those with CLL who had at least 1 prior therapy and required treatment by International Working Group on CLL (IWCLL) 2008 Guidelines (Hallek, M Blood 2008), had Eastern Cooperative Oncology Group Performance Status <3, had platelets ≥50,000/mm3, and had adequate organ function. Primary endpoints were to determine maximal tolerated dose (MTD), describe toxicity, and characterize pharmacokinetics (PK). A secondary endpoint was to explore efficacy. An accelerated titration design was used in which 1 pt was accrued to the first two dose levels provided there were no dose limiting toxicities (DLT) or ≥ grade 2 adverse events (AE), and then a standard 3×3 design was employed from dose level 3 forward. Dose levels included 0.3, 1, 3, 6, 9, and 12 mg/kg with an expansion to a total of 16 pts at the MTD. XmAb5574 was administered as an intravenous infusion on days 1, 4, 8, 15, and 22 of cycle (C) 1, and on days 1, 8, 15, and 22 of C2. Toxicity was assessed using the National Cancer Institute's Common Criteria for Adverse Events v4.0 for non-hematologic toxicity, and IWCLL 2008 guidelines for hematologic toxicity. Disease response assessment by physical exam was performed on C1D28, C2D28, and 4, 8, and 12 weeks after the end of C2. Radiographic assessment was performed C2D28. 27 pts were enrolled to this phase I trial. The median age of all pts was 66 years (range 40–84). The pts were generally high risk: 14 (52%) had high-risk disease by Rai stage, 8 (30%) had del(11q22.3) and 10 (37%) had del(17p13.1) by FISH, and 24 (89%) had IgVH unmutated disease. The median number of prior therapies was 4 (range 1–14). Toxicity with this agent was modest. Dose escalation continued without dose limiting toxicity (DLT) until the highest dose level, in which one patient experienced grade 4 neutropenia associated with febrile neutropenia which required dose discontinuation. 100% of patients experienced any AE, with the majority of AE being grade 1–2. The most common AEs were infusion reactions in 18 patients (67%), all of which were grade 1 or 2. Treatment-related Grade 3 or 4 AEs occurred in 5 pts (19%), and included neutropenia (n=3), thrombocytopenia (n=2), increased aspartate aminotransferase (AST) (n=1), febrile neutropenia (n=1), and tumor lysis syndrome (n=1). All were on the 12 mg/kg dose level except one pt receiving 1mg/kg who experienced neutropenia. Overall response rate by IWCLL 2008 criteria is 11%, all of which have been partial responses (PR). Using IWCLL 1996 response criteria which does not include CT scan assessment of disease resulted in a PR in 13 pts (42%). Only 2 pts had PD at the 8 week evaluation point. Responses occurred at the 6, 9, and 12 mg/kg dose levels. All objective responses were in pts categorized as CLL as opposed to SLL, and no patients with lymph nodes >5cm responded. PK was best modeled by a two-compartment model. Half-life was 14 days, with clearance 5mL/day/kg that was not dose-dependent. Across the dose range, area under the curve increased in a dose-proportional manner, while maximum concentration increased in a less than proportional manner. A steady-state was reached at or before infusion 9. XmAb5574 shows acceptable toxicity and signs of preliminary efficacy in patients with high-risk, heavily pretreated CLL. These results justify movement into phase II study in CLL as well as other B cell malignancies. Modest toxicity, in particular infectious toxicity, will potentially allow combinations with other active agents in CLL. Disclosures: Enoch: Xencor, Inc.: Employment. Foster:Xencor, Inc: Consultancy.

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Safety and Efficacy of Combined Ruxolitinib and Decitabine in Patients with Blast-Phase MPN and Post-MPN AML: Results of a Phase I Study (Myeloproliferative Disorders Research Consortium 109 trial)

Blood ◽

10.1182/blood.v128.22.1124.1124 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1124-1124 ◽

Cited By ~ 10

Author(s):

Raajit K. Rampal ◽

John O. Mascarenhas ◽

Heidi E. Kosiorek ◽

Dmitriy Berenzon ◽

Elizabeth Hexner ◽

...

Keyword(s):

Bone Marrow ◽

Adverse Events ◽

Phase I ◽

Peripheral Blood ◽

Research Funding ◽

Phase I Trial ◽

Fixed Dose ◽

Hematologic Toxicity ◽

Blast Phase ◽

Grade 3

Abstract Background: The Philadelphia chromosome negative myeloproliferative neoplasms (MPN) includePolycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). These stem cell disorders carry a propensity to evolve into acute myeloid leukemia (MPN-blast phase [BP] or post-MPN AML) with a dismal prognosis not meaningfully improved by conventional anti-leukemia therapy. Thus, MPN-BP is an urgent unmet clinical need. Responses in patients with MPN-BP to hypomethylating agents and single agent ruxolitinib have been reported. More recently, combination of ruxolitnib and decitabine has demonstrated synergistic activity in vitro in cells derived from patients with MPN-BP and from a murine model of MPN-BP (Rampal et al PNAS 2014). These observations led us to explore the safety of combined decitabine and dose escalation of ruxolitinib in MPN-BP. Objective: To establish the maximum tolerated dose (MTD) of ruxolitinib in combination with a fixed dose of decitabine (DEC-RUX). Methods: We conducted an open label Phase I trial in patients with MPN acceleration phase (AP) as defined by 10%-19% blasts in the peripheral blood or bone marrow or a diagnosis of MPN-BP as defined by ≥ 20% blasts in the blood or bone marrow, following a previous diagnosis of ET, PV or PMF. Patients were enrolled in a standard 3+3 phase I design with an MTD defined as a dose <33% DLT. Ruxolitinib was administered at doses of 10mg, 15mg, 25mg, or 50mg every 12 hours in combination with concurrent decitabine at a dose of 20mg/m2 daily intravenously over 5 days and repeated every 28 days. Adverse events were assessed using the NCI CTCAE v. 4.0. DLTs were defined as Grade 3 or higher non-hematologic toxicity events not clearly related to disease and grade 4 hematologic events with a bone marrow cellularity of ≤5% and no evidence of leukemia. Response assessment was carried out every cycle using modified Cheson criteria: CR required 0% peripheral blood blasts, WBC ≥4x109/L, hemoglobin ≥10g/L, and platelets ≥100x109/L; CRi required 0% peripheral blood blasts with incomplete count recovery; and PR required ≥50% decrease in peripheral blood blasts regardless of blood counts. Results: A total of 21 patients were accrued to study (Table 1). The median age was 63 years (range 48-88). 52% carried a diagnosis of MPN-AP, and 48% carried a diagnosis of MPN-BP. 29% of patients and 24% of patients had prior exposure to ruxolitinb and decitabine, respectively. The median number of cycles received varied from 10.5 cycles in the 10mg BID cohort to 2 and 2.5 cycles in the 25mg BID and 50mg BID cohorts, respectively (Table 2). The most common Grade 3/4 non-hematologic AEs observed were due to infection in all dosing cohorts. In terms of hematologic toxicity, treatment emergent Grade 3/4 anemia was observed in 1 patient in each of the 10mg BID, 15mg BID, and 50mg BID cohorts. Grade 3/4 leukopenia was observed in only 1 patient at the 50mg BID cohort, and Grade 3/4 thrombocytopenia was observed in 2 patients in the 10mg BID cohort and 1 patient in the 15mg BID cohort. DLT rate was below 33% for all dose levels so the MTD was not reached. The most common reason for ending study treatment was toxicity/adverse events (33%) followed by disease progression (22%). 9 patients died during study or follow-up. Of those, 5 (56%, 2 in 10mg BID cohort, 1 in 15mg BID cohort, 2 in 50mg BID cohort) died of infection, 3 (33%, 1 in each of 10mg, 25mg, and 50mg BID cohorts) of progressive disease, and 1 (11%, 25mg BID cohort) of hemorrhage. The median overall survival for patients on study was 10.4 months (95% CI 3.3 mo - not reached). CR/CRi as best response was observed in 7/21 patients (33%, 95% CI 15-57%; 2 CR, 5 CRi; Table 2). Conclusions: DEC-RUX combination therapy was safely administered to patients with MPN-AP/BP and an MTD was not reached. Based on pre-clinical data, observed safety profile, duration of treatment, and clinical responses in this phase I trial, the Recommended Phase II Dose of RUX was selected as 25mg BID for an induction cycle followed by 10mg BID in all ensuing cycles. Molecular and bone marrow pathology responses will be presented at the meeting. Disclosures Mascarenhas: Promedior: Research Funding; CTI Biopharma: Research Funding; Novartis: Other: DSMB , Research Funding; Janssen: Research Funding; Roche: Research Funding; Incyte: Other: Clinical Trial Steereing Committee, Research Funding. Hexner:Blueprint medicines: Consultancy; Novartis: Research Funding. Abboud:Alexion: Honoraria; Takeda: Honoraria; Novartis: Research Funding; Teva: Research Funding, Speakers Bureau; Pfizer: Research Funding; Merck: Research Funding; Pharmacyclics: Honoraria; Baxalta: Honoraria; Seattle Genetics: Research Funding; Gerson and Lehman Group: Consultancy; Cardinal: Honoraria. Levine:Novartis: Consultancy; Qiagen: Membership on an entity's Board of Directors or advisory committees. Mesa:Promedior: Research Funding; Novartis: Consultancy; Incyte: Research Funding; Celgene: Research Funding; Galena: Consultancy; Ariad: Consultancy; Gilead: Research Funding; CTI: Research Funding.

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A phase I trial of chemoimmunotherapy combining bacillus Calmette-Guerin (BCG) and intravesical gemcitabine for patients with BCG-relapsing high-grade nonmuscle-invasive bladder cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.tps509 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. TPS509-TPS509

Author(s):

Manuel R. De Jesus Escano ◽

Daniel D. Sjoberg ◽

Melissa McCarter ◽

Marlena McGill ◽

Alvin Goh ◽

...

Keyword(s):

Bladder Cancer ◽

Adverse Events ◽

Phase I ◽

Phase I Trial ◽

Maximum Tolerated Dose ◽

Invasive Bladder Cancer ◽

High Grade ◽

Continual Reassessment Method ◽

Intravesical Treatment ◽

Continual Reassessment

TPS509 Background: Intravesical BCG is the most effective treatment for high-grade non-muscle invasive bladder cancer (NMIBC), yet recurrences are common. Patients with BCG-relapsing NMIBC are often re-treated with BCG or BCG with interferon (IFN) with an expected response rate of only 40–60%. Several studies show that a major mechanism of resistance to BCG is high levels of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in the pretreatment tumor microenvironment. Gemcitabine is a commonly used intravesical treatment for NMIBC that, in addition to direct anti-tumor cytotoxic effects, may also reduce MDSCs and Tregs. Prior trials combining BCG with intravesical mitomycin C have shown improved efficacy over BCG alone but with higher toxicity. While gemcitabine has been shown to be better tolerated than mitomycin as an intravesical treatment, no study has looked at combined BCG and intravesical gemcitabine. We hypothesize that combining BCG and intravesical gemcitabine will be well tolerated and result in higher response rates by reducing levels of MDSCs and Tregs. A novel aspect of our trial design is the use of a modified continual reassessment method to more accurately identify the maximum tolerated dose instead of the traditional 3 + 3 design used in most NMIBC phase I trials. Methods: This is an investigator-initiated phase I trial (NCT04179162) that will study the safety of alternating intravesical gemcitabine and BCG. Inclusion and exclusion criteria are designed so most patients who would ordinarily be re-treated with BCG or BCG/IFN would be eligible. Patients must have recurrent high-grade NMIBC within 24 months of their last BCG treatment without meeting the criteria for BCG-unresponsive NMIBC. Intravesical gemcitabine is given twice a week on weeks 1, 4, 7, and 10, for a total of 8 doses. BCG (50 mg) is given once a week on weeks 2, 3, 5, 6, 8, and 9, for a total of 6 doses. The trial is monitored using a modified continual reassessment method with increasing dose levels of gemcitabine (500 mg, 1,000 mg, 1,500 mg, and 2,000 mg) being evaluated. Adverse events are assessed using the Common Terminology Criteria for Adverse Events version 5.0. The primary objective is to determine the maximum tolerated dose of this combination to inform our planned phase II trial. Correlative studies will look at the immunomodulating effects of gemcitabine by evaluating changes in immune cell populations in serial blood and urine specimens. Tissue and urine will also be evaluated for molecular determinants of response and resistance to the combination. The trial is open to enrollment with 10 of 25 planned patients accrued to date. Clinical trial information: NCT04179162.

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Phase I trial of intratumoral PVSRIPO in patients with unresectable, treatment-refractory melanoma

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-002203 ◽

2021 ◽

Vol 9 (4) ◽

pp. e002203

Author(s):

Georgia M Beasley ◽

Smita K Nair ◽

Norma E Farrow ◽

Karenia Landa ◽

Maria Angelica Selim ◽

...

Keyword(s):

Adverse Events ◽

Phase I ◽

Phase I Trial ◽

Clinical Investigation ◽

Objective Response ◽

Complete Response ◽

Primary Objective ◽

Mitogen Activated Protein Kinase ◽

Open Label ◽

Serious Adverse Events

BackgroundWhile programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) antagonists have improved the prognosis for many patients with melanoma, around 60% fail therapy. PVSRIPO is a non-neurovirulent rhinovirus:poliovirus chimera that facilitates an antitumor immune response following cell entry via the poliovirus receptor CD155, which is expressed on tumor and antigen-presenting cells. Preclinical studies show that oncolytic virus plus anti-PD-1 therapy leads to a greater antitumor response than either agent alone, warranting clinical investigation.MethodsAn open-label phase I trial of intratumoral PVSRIPO in patients with unresectable melanoma (American Joint Committee on Cancer V.7 stage IIIB, IIIC, or IV) was performed. Eligible patients had disease progression on anti-PD-1 and V-raf murine sarcoma viral oncogene homolog B (BRAF)/mitogen activated protein kinase kinase (MEK) inhibitors (if BRAF mutant). The primary objective was to characterize the safety and tolerability of PVSRIPO. Twelve patients in four cohorts received a total of 1, 2 or 3 injections of PVSRIPO monotherapy, with 21 days between injections.ResultsPVSRIPO injections were well tolerated with no serious adverse events (SAEs) or dose-limiting toxicities (DLTs) reported. All adverse events (AEs) were grade (G) 1 or G2 (G1 pruritus most common at 58%); all but two PVSRIPO-treatment related AEs were localized to the injected or adjacent lesions (n=1 G1 hot flash, n=1 G1 fatigue). Four out of 12 patients (33%) achieved an objective response per immune-related response criteria (two observations, 4 weeks apart), including 4/6 (67%) who received three injections. In the four patients with in-transit disease, a pathological complete response (pCR) was observed in two (50%) patients. Following study completion, 11/12 patients (92%) reinitiated immune checkpoint inhibitor-based therapy, and 6/12 patients (50%) remained without progression at a median follow-up time of 18 months.ConclusionIntratumoral PVSRIPO was well tolerated. Despite the limited number of PVSRIPO treatments relative to the overall lesion burden (67% patients>5 lesions), intratumoral PVSRIPO showed promising antitumor activity, with pCR in injected as well as non-injected lesions in select patients.Trial registration numberNCT03712358

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Phase I Trial of Belinostat and Bortezomib in Patients with Relapsed or Refractory Acute Leukemia, Myelodysplastic Syndrome, or Chronic Myelogenous Leukemia in Blast Crisis - One Year Update

Blood ◽

10.1182/blood.v120.21.3588.3588 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3588-3588

Author(s):

Beata Holkova ◽

Prithviraj Bose ◽

Mary Beth Tombes ◽

Ellen Shrader ◽

Wen Wan ◽

...

Keyword(s):

Adverse Events ◽

Acute Leukemia ◽

Myelodysplastic Syndrome ◽

Phase I ◽

Chronic Myelogenous Leukemia ◽

Dose Level ◽

Phase I Trial ◽

Blast Crisis ◽

Myelogenous Leukemia ◽

Acute Leukemias

Abstract Abstract 3588 Although reports of synergistic interactions between proteasome and histone deacetylase (HDAC) inhibitors in acute leukemias have been limited, they are well described in B-cell malignancies (e.g., myeloma and lymphoma). Nevertheless, preclinical findings have shown striking synergism between the HDAC inhibitor belinostat (previously PXD-101) and the proteasome inhibitor bortezomib, administered at low (sub-micromolar) concentrations, in cultured and primary acute myeloid leukemia (AML) and acute lymphocytic leukemia cells (Dai Y et al. Br J Haematol. 2011). These findings prompted initiation of a phase I trial, using a 3+3 design, with the primary objective of determining the maximum tolerated dose (MTD) for the combination of bortezomib and belinostat in patients with relapsed or refractory acute leukemia, myelodysplastic syndrome (MDS), or chronic myelogenous leukemia in blast crisis (CML-BC). To date, 25 patients with the following disease types have been treated: acute leukemia (n=19), MDS (n=4), and CML-BC (n=2). The male:female ratio was n=11 (44%):14 (56%); the median age was 62 (range 27–83) years; ECOG performance scores ranged from 0–2; and the median number of prior therapies was 2 (range 1–5). The schedule of administration was belinostat, 30 minutes intravenous (IV) infusion, on days 1–5 and 8–12; and bortezomib, IV bolus, preceding belinostat on days 1, 4, 8, 11; on a 21-day cycle. Dose levels were, in mg/m2(bortezomib/belinostat): 1.0/500 (n=6); 1.3/500 (n=6); 1.3/650 (n=4); 1.3/850 (n=3); 1.3/1000 (n=4); 1.3/1200 (n=2). The study is currently enrolling to dose level 6 (1.3/1200). No dose-limiting toxicities (DLTs) have been observed to date. Non-DLT ≥ grade 2 (CTCAE version 4) treatment-related adverse events have included: fatigue (grade 2, 36%), leukopenia (grade 4, 12%), nausea (grade 2, 12%), peripheral sensory neuropathy (grade 2, 12%), and thrombocytopenia (grade 3, 20%). No serious adverse events have occurred at an unexpected frequency or severity. Two deaths have occurred due to disease progression, and one death has occurred due to a cerebrovascular accident that was related to pre-existing comorbidities and not to study-therapy. Of the 25 patients treated, 22 have been evaluable for response, 2 are too early to evaluate, and 1 patient was not evaluable for response. There have been 2 partial responses (PRs) and 1 complete response (CR) in this heavily pretreated population. The CR was achieved at dose level 1 in a patient with biphenotypic acute leukemia refractory to 7+3 and Flag-IDA. The patient proceeded to allogeneic hematopoietic stem cell transplantation (SCT) after 4 cycles of treatment. In addition, 1 patient with CML-BC had stable disease (SD) by protocol criteria but a CR with incomplete blood count recovery (CRi) by standard criteria, and is undergoing evaluation for allogeneic hematopoietic SCT. The patient is currently in cycle 8 at dose level 4. One of the PRs was achieved in a patient with AML transformed from MDS (2 prior regimens); after 4 cycles of treatment at dose level 5, the patient proceeded to allogeneic hematopoietic SCT. The second PR was achieved in an AML patient after cycle 2; a bone marrow biopsy revealed chronic myelomonocytic leukemia, and the response was deemed sufficient to proceed to allogeneic hematopoietic SCT. Also of note, a patient with AML transformed from MDS is currently on treatment in cycle 5 at dose level 5 with SD. An additional 6 patients have had SD, and 11 patients have had progressive disease. Correlative studies examining pre- and post-treatment leukemic blast expression of nuclear RelA, Bim, Bcl-xL, and XIAP are ongoing. Collectively, these findings indicate that a regimen combining belinostat and bortezomib is well tolerated in patients with relapsed or refractory acute leukemia, MDS, or CML-BC and shows evidence of activity. The MTD has not yet been reached. Pending identification of the MTD, phase II evaluation of this therapeutic strategy, should determine its activity more definitively. Disclosures: No relevant conflicts of interest to declare.

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Weight Loss With a Novel Peptide YY Analogue for Obesity: A Randomised, Placebo-Controlled Phase I Trial

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.061 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A32-A32

Author(s):

Tricia Tan ◽

James Minnion ◽

Bernard Chong Eu Khoo ◽

Laura-Jayne Ball ◽

Reshma Malviya ◽

...

Keyword(s):

Body Weight ◽

Food Intake ◽

Adverse Events ◽

Glucose Tolerance ◽

Phase I ◽

Phase I Trial ◽

Extended Release ◽

Peptide Yy ◽

Secondary Outcome ◽

Multiple Doses

Abstract Background: Obesity and its co-morbidities remain a prime driver of global morbidity and mortality. Current therapies for obesity are limited in efficacy and durability, have serious adverse effects or are not scalable to the numbers required to treat this widespread disease. Gut hormones such as peptide YY (PYY) have emerged as candidate therapies for obesity which activate natural satiety pathways, reduce food intake and therefore body weight. We report the results from a Phase I trial of a PYY analogue, Y14, in overweight volunteers. Methods: In a first time in human Phase I randomized placebo-controlled trial, an extended-release formulation of Y14 with zinc chloride for subcutaneous injection, utilizing various Zn:peptide molar ratios, was tested. Part A of the trial was a partially blinded single ascending dose study. Part B was double-blinded and tested multiple ascending doses given at 7–14 day intervals over the course of 28 days with up to 5 doses given per subject. The primary outcome was the safety and tolerability of extended-release Y14; the secondary outcome was to assess its pharmacokinetics. Exploratory outcomes included the assessment of food consumption, body weight and glucose tolerance in response to 75g oral glucose load after multiple doses of Y14. [ClinicalTrials.gov NCT03673111]. Findings: Between Apr 11, 2017, and Dec 24, 2018 44 participants were enrolled into Part A of the trial and 24 into Part B and were included in the full analysis and safety datasets. The multiple doses of Y14 given in Part B led to significant mean placebo-subtracted reductions in body weight of 2.76 to 3.59 kg at 31 days after the first dose, in association with profound reductions in food intake and no evidence of tachyphylaxis. No significant changes in glucose tolerance were detected. The most common adverse events were nausea, vomiting and injection site reactions. No serious adverse events occurred. The pharmacokinetic characteristics of extended-release Y14 were compatible with administration every 7–14 days. Interpretation: Our results support the continued development of Y14 as a novel treatment for obesity. Funding: UK Medical Research Council Developmental Pathway Funding Scheme.

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Open-label extension study of the RNAi therapeutic ALN-VSP02 in cancer patients responding to therapy.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.3062 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 3062-3062 ◽

Cited By ~ 2

Author(s):

Maria Alsina ◽

Josep Tabernero ◽

Geoffrey Shapiro ◽

Howard Burris ◽

Jeffrey R. Infante ◽

...

Keyword(s):

Endometrial Cancer ◽

Adverse Events ◽

Phase I ◽

Cell Carcinoma ◽

Phase I Trial ◽

Tumor Regression ◽

Average Length ◽

Phase 1 ◽

Extension Study ◽

Phase Ii Trials

3062 Background: ALN-VSP02 is an RNA interference (RNAi) therapeutic comprised of lipid nanoparticle-formulated small interfering RNAs targeting vascular endothelial growth factor (VEGF)-A and kinesin spindle protein (KSP). In a phase 1 trial, ALN-VSP02 administered as an iv infusion q2 wks was well-tolerated and showed evidence of anti-VEGF pharmacology and antitumor activity. Methods: Patients treated on the phase I trial with stable disease (SD) or better after 4 months (8 doses) were eligible to continue on an extension study until disease progression. Main objectives included continued evaluation of safety/tolerability and assessment of disease response. Results: Seven of 37 patients (18.9%) evaluable for response went onto the extension study, including 1 of 7 (14.2%) at 0.4 mg/kg, 2 of 5 (40%) at 0.7 mg/kg, and 4 of 11 (36.3%) at 1.0 mg/kg. All had progressed after one or more prior therapies. Tumor types included head and neck squamous cell carcinoma, angiosarcoma, endometrial cancer, renal cell carcinoma (RCC, N=2), and pancreatic neuroendocrine tumor (PNET, N=2). At the time of enrollment, 6 had SD and one (endometrial cancer with multiple liver metastases) had an unconfirmed partial response (PR). The average length of time on treatment (including phase I and extension studies) was 9.5 months (range 5-19). As of January 2012, 3 patients remain on study, including the endometrial cancer patient with an ongoing PR who has had >80% tumor regression after 19 months of treatment at 0.7 mg/kg and two patients with RCC and PNET with continued SD after nearly 1 year of treatment at 1.0 mg/kg. The other patients with RCC and PNET at 1.0 mg/kg with SD came off after 8.5 and 5.5 months, respectively, for adverse events that included fatigue or elevated alkaline phosphatase. A decrease in spleen volume, likely an on-target effect and not associated with any adverse events, occurred to a greater degree on the extension study than on the phase I trial and was most pronounced in patients receiving ≥ 12 doses. Conclusions: ALN-VSP02 has preliminary activity against endometrial cancer, RCC and PNET and a favorable safety profile that permits chronic dosing. Phase II trials are warranted in these and other VEGF-overexpressing tumors.

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Phase I trial evaluating safety and efficacy of intratumorally administered allogeneic monocyte-derived cells (ilixadencel) in advanced gastrointestinal stromal tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.5_suppl.15 ◽

2020 ◽

Vol 38 (5_suppl) ◽

pp. 15-15

Author(s):

Alex Karlsson-Parra ◽

Robin Fröbom ◽

Erik Berglund ◽

David Berglund ◽

Inga-Lena Nilsson ◽

...

Keyword(s):

Adverse Events ◽

Phase I ◽

Stable Disease ◽

Phase I Trial ◽

Second Line ◽

Safety And Efficacy ◽

Recist 1.1 ◽

Choi Criteria ◽

The Subject ◽

Third Line

15 Background: Ilixadencel is a cell-based, off-the-shelf product based on allogeneic monocyte-derived inflammatory cells aimed to prime an anti-cancer immune response when injected intratumorally. The present single arm Phase I trial (ClinicalTrials.gov Identifier: NCT02686944) assessed the safety and efficacy of ilixadencel in subjects with progressing advanced/metastatic GIST despite ongoing treatment with second or later lines of tyrosine kinase inhibitors (TKI). Methods: Three GIST patients were progressing while on sunitinib (second-line), one on regorafenib (third-line), and two on pazopanib (fifth-line). Treatment consisted of two intratumoral injections of ilixadencel two weeks apart. If further tumor progression was observed at the 3-month follow up, the TKI was withdrawn and the subject performed an end of study visit. If stable disease or objective response was observed, the subject continued with the TKI until progression of disease. Results: No severe adverse events were found to be related to ilixadencel administration. Four patients showed continued tumor progression at 3 months per RECIST 1.1 and Choi criteria. Two patients had stable disease as best response; one of these patients (on third-line regorafenib) progressed at 12 months and the other (a patient on second-line sunitinib) showed continued stable disease at end of study (12 months) as per RECIST 1.1. These two patients also developed a partial response as per Choi criteria with a duration of 3 and 6 months, respectively. No serious adverse events were found to be possibly or probably related to ilixadencel administrtion. Conclusions: Ilixadencel treatment presented an acceptable safety profile among advanced GIST patients who developed resistance to TKI. Encouraging radiological tumor responses were detected in 33% of treated patients, supporting further investigation. Clinical trial information: 02686944.

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