scholarly journals EPCT-04. RESULTS OF A PHASE 1 STUDY OF THE ONCOLYTIC ADENOVIRUS DNX-2401 WITH RADIOTHERAPY FOR NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i47-i47
Author(s):  
Marc Garcia-Moure ◽  
Jaime Gállego Pérez-Larraya ◽  
Ana Patiño ◽  
Marisol Gonzalez-Huarriz ◽  
Chris Jones ◽  
...  
Keyword(s):  
Phase 1 ◽  
Study Drug ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Oncolytic Adenovirus ◽  
Clinical Activity ◽  
Karnofsky Performance Score ◽  
Newly Diagnosed ◽  
Pontine Glioma ◽  
Tumor Biopsy ◽  
Grade 3

Abstract Background A Phase 1, single center study is ongoing to evaluate the conditionally replicative oncolytic adenovirus, DNX-2401 (tasadenoturev), followed by radiotherapy (RT) in pediatric patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG). Methods Patients 1–18 years with newly diagnosed DIPG with no prior treatment, Lansky/Karnofsky performance score ≥ 70, and adequate organ function were enrolled. A tumor biopsy was performed followed by a single intratumoral injection of 1e10-5e10 virus particles (vp) DNX-2401. Conventional radiotherapy was initiated within 1 month of DNX-2401 administration. Results Enrolled subjects (n=12) had a median age of 9 (range 3–18) and performance scores of 90–100 (n=4; 33%) or 70–80 (n=8; 67%). As part of a dose escalation design, subjects were treated with 1e10 vp (n=4) or 5e10 vp DNX-2401 (n=8), which was then followed by standard RT in 11 of 12 subjects (92%). No dose-limiting toxicities were observed and the treatment regimen was well-tolerated. Adverse events (AEs) have been primarily mild to moderate and consistent with underlying disease. The most commonly reported AEs (≥ 5 subjects), regardless of study drug relationship, include headache, asthenia, vomiting, anemia, leukocytosis, and fever. Two SAEs have been reported including grade 3 lymphopenia and grade 3 abdominal pain. Tumor reductions have been observed and efficacy evaluations are ongoing. As of 09Dec2020, 12-month survival (OS-12) was 71% and 4 of 12 patients had survived > 20 months. Four subjects continue to be followed for survival. Correlative analysis of tumor biopsy and peripheral samples is ongoing. Conclusions DNX-2401 followed by RT can be safely administered to pediatric subjects with newly diagnosed DIPG; clinical activity and preliminary survival are encouraging.

CTIM-08. SAFETY, EFFICACY, AND SURVIVAL RESULTS FROM A PHASE 1 STUDY OF THE ONCOLYTIC ADENOVIRUS DNX-2401 FOLLOWED BY STANDARD OF CARE RADIOTHERAPY FOR NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi50-vi51
Author(s):  
Jaime Gállego Pérez-Larraya ◽  
Marc Garcia-Moure ◽  
Ana Patiño-García ◽  
Marisol González-Huarriz ◽  
Jasper Van der Lugt ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase 1 ◽  
Standard Of Care ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Oncolytic Adenovirus ◽  
Newly Diagnosed ◽  
Pontine Glioma ◽  
Serious Adverse Events ◽  
Tumor Biopsy ◽  
Grade 3

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is the most lethal pediatric brain tumor. Median overall survival (OS) with standard of care radiation therapy (RT) is approximately 8-10 months and 2-year survival is < 10%. A Phase 1 single-center study was conducted to evaluate the oncolytic adenovirus, DNX-2401 (tasadenoturev), followed by RT for DIPG. METHODS Newly-diagnosed DIPG patients 1-18 years old received a tumor biopsy through the cerebellar peduncle followed by intratumoral injection of 1e10 – 5e10 vp DNX-2401 and conventional RT 1-3 weeks later. RESULTS Subjects were enrolled (n=12) from December 2017 to January 2020 and had a median age of 9 years (range 3-18) and Lansky/Karnofsky performance scores of 90-100 (n=4; 33%) or 70-80 (n=8; 67%). Genetic assessment was completed for 11 subjects (92%) and histone 3 K27M mutations were identified in 10 subjects, including H3F3A (n=8), HIST2H3C (n=1), and HIST1H3B (n=1); 1 subject was H3 wildtype (n=1). TP53 mutations were identified in 5 subjects (42%). DNX-2401 was administered followed by RT (n=11; 92%). No dose-limiting toxicities were observed and the treatment regimen was well-tolerated. The most commonly reported adverse events (≥ 5 subjects), regardless of study drug relationship, include asthenia, headache, vomiting, pyrexia, and neurological deterioration. Three serious adverse events were reported including grade 3 abdominal pain, grade 3 lymphopenia, and grade 3 clinical deterioration. Tumor reductions were reported for 9 subjects (75%), including 2 confirmed (17%) and 2 unconfirmed (17%) responses per RAPNO criteria. As of the data cutoff, median OS is 19.7 months and OS-24 is 32% with follow-up ongoing for 3 subjects (26.9, 25.6, 13.7 months). CONCLUSIONS DNX-2401 followed by RT can be safely administered to DIPG. Survival outcomes are encouraging, thus warranting further evaluation in a Phase 2 study.

scholarly journals DDRE-21. PNOC015: PHASE 1 STUDY OF MTX110 DELIVERED BY CONVECTION ENHANCED DELIVERY (CED) IN CHILDREN WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) PREVIOUSLY TREATED WITH RADIATION THERAPY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii66-ii66
Author(s):  
Sabine Mueller ◽  
Cassie Kline ◽  
Javier Villanueva-Meyer ◽  
Carly Hoffman ◽  
Shannon Raber ◽  
...  
Keyword(s):  
Phase 1 ◽  
Volume Ratio ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Newly Diagnosed ◽  
Convection Enhanced Delivery ◽  
Catheter Position ◽  
Pharmacodynamic Effects ◽  
Distribution Volume Ratio ◽  
Previously Treated ◽  
Grade 3

Abstract OBJECTIVE To determine safety and distribution of MTX110 delivered by CED in newly diagnosed DIPG patients. METHODS DIPG patients (3–21 years) were enrolled after radiation. CED of MTX110 combined with gadoteridol was completed based on dose levels (DL) (30–90 µM with volumes ranging from 3 cc (single dose) to 2 consecutive doses of 6 cc; total number of DL=7). Catheter position was chosen to maximize tumor coverage. Distribution of infusate was monitored with real-time MR imaging. Repeat CED was performed every 4–8 weeks if tolerated. Quality of life (QOL) assessments using PedsQL Generic Core and Brain Tumor modules were obtained at baseline (n=5), 3-months (n=3), and end of therapy (n=2). Single-cell RNA sequencing and analysis of histone modifications was performed to assess pharmacodynamic effects on DIPG cells. RESULTS Between May 2018-Dec 2019, 6 patients were enrolled (median age 8 years, range 5–21). Dose limiting toxicities included: grade 3 gait disturbance (DL7; cycle 1); grade 3 muscle weakness/vagus nerve disorder (DL5; cycle 4) and grade 2 intolerable dysphagia (DL7; cycle 4). Twelve CED procedures were completed at DL7 and repeated cycles ranged from 2 to 7. Infusion to distribution volume ratio was approximately 1:3.5. There were no significant changes in self-reported QOL. Parent ratings of patients’ worry (p = 0.04) and overall QOL (p = 0.03) significantly decreased at 3-months. CONCLUSION Repeat CED of MTX110 at the highest dose is tolerable. Tissue concentrations are likely to be substantially higher compared to oral dosing. Pharmacodynamic effects will be presented.

The combination of venetoclax, lenalidomide, and rituximab in patients with newly diagnosed mantle cell lymphoma induces high response rates and MRD undetectability.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7505-7505
Author(s):  
Tycel Jovelle Phillips ◽  
Alexey Valeryevich Danilov ◽  
David Alan Bond ◽  
Alex Francisco Herrera ◽  
Kami J. Maddocks ◽  
...  
Keyword(s):  
Phase 1 ◽  
Safety Data ◽  
Standard Of Care ◽  
Primary Objective ◽  
Clinical Activity ◽  
Newly Diagnosed ◽  
Grade 5 ◽  
Unrelated Condition ◽  
Mantle Cell ◽  
Grade 3

7505 Background: MCL is a rare lymphoma without a standard of care but several regimens have demonstrated clinical activity, the majority based on traditional chemotherapy. We hypothesized that adding venetoclax (V) to R2 would be safe and effective in MCL pts irrespective of age, morphology or stage. Here we present safety and efficacy data from the on-going phase 1b study of R2 + V in pts with newly diagnosed MCL. Methods: This multi-center phase 1 study (NCT03523975) enrolled pts aged ≥18 yrs with untreated MCL. The primary objective was to characterize the safety and tolerability of R2 + V and determine the MTD. During induction (12 months (m)) pts received lenalidomide (L) 20 mg daily on day 1-21, Rituximab (R) was given weekly during c1 then on day 1 of every even cycle, V was escalated over 4 weeks to 400 mg beginning day 8. Each cycle is 28 days (d). The DLT period was 42 d beginning C1D8. In maintenance, R every 8 weeks for 36m, L at 10 mg or half of last dose during induction for 24 m and V for minimum 12 m. No pts have been transplanted. Pts with progression (PD) came off study. MRD was analyzed in parallel with scans during induction by clonoSEQ assay (Adaptive Biotechnologies). Results: As of Feb. 1st, 2021, we have enrolled all 28 planned pts on study. Pt characteristics/responses are summarized in Table. Among the 28 pts who have received at least one dose, the median treatment duration so far is 278d (IQR 170-560), with 24 pts still on treatment (Tx). 1 pt is off from a unrelated condition. All pts escalated to V 400 mg w/o any DLTs noted. Treatment-emergent adverse events (TEAEs) were reported in 100% of pts, and grade 3+ TEAEs were reported in 26 (93%) patients. The most common all-grade TEAEs (≥50% of pts), regardless of relationship to study Tx, were fatigue, neutropenia and diarrhea. Grade ≥3 TEAEs reported in ≥50% pts were neutropenia (68%) and thrombocytopenia (50%). No pts have withdrawn or d/c Tx due to AEs. There was one grade 5 event, in a non-evaluable pt, related to a PE that occurred prior to DLT period. In the 28 evaluable pts the ORR (CR/PR) was 96% (27/28 pts) with CR/CRu of 89%. Of the responding pts, two had PD, one w/ CR and one w/ PR. All pts with PD had baseline TP53 mutation. MRD testing was successful in all pts. At time of submission 20 of 28 (71%) were MRD - at 10-6. Conclusions: Interim results show that at the MTD the combination of V 400 mg daily, L 20 mg, with R is safe with a manageable toxicity profile and a high ORR and MRD - in pts with newly diagnosed MCL. Safety data is consistent with the AE profile noted for each drug without any unexpected or unique AEs. Updated results including BH3 profiling will be presented at the meeting. Clinical trial information: NCT03523975. [Table: see text]

The Bruton's Tyrosine Kinase Inhibitor, PCI-32765, Is Well Tolerated and Demonstrates Promising Clinical Activity In Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL): An Update on Ongoing Phase 1 Studies

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 57-57 ◽  
Author(s):  
Jan A. Burger ◽  
Susan O'Brien ◽  
Nathan Fowler ◽  
Ranjana Advani ◽  
Jeff Porte Sharman ◽  
...  
Keyword(s):  
B Cell ◽  
Phase 1 ◽  
Study Drug ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
B Cell Malignancies ◽  
Employment Equity ◽  
Bcr Signaling ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 57 Introduction: Bruton's tyrosine kinase (Btk) is a downstream mediator of B-cell receptor (BCR) signaling and is not expressed in T-cells or NK-cells. As such, Btk represents an ideal therapeutic target for B-cell malignancies dependent upon BCR signaling. Chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) has been reported to have constitutively active BCR signaling. PCI-32765 is a potent, selective, irreversible and orally bioavailable small molecule inhibitor of Btk that has pre-clinical activity in B-cell malignancies (Proc Natl Acad Sci 2010;107(29):13075-80). PCI-32765 was therefore moved forward to a Phase 1 study in B-cell malignancies including patients (pts) with CLL/SLL. A subsequent CLL/SLL-specific Phase 1b study was initiated to further explore safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of PCI-32765. This report includes a composite summary of the CLL/SLL experience in both of these studies. Pts and Methods: Pts with CLL/SLL who had relapsed or refractory disease after >1 prior treatment regimens were eligible for treatment in each of the studies whereas the second Phase 1b study also included a cohort of elderly pts (aged ≥ 65 years) with CLL/SLL who required treatment and were “treatment-naive”. Responses were assessed by the investigator using the International Working Group CLL criteria (Hallek et al, Blood 2008 for pts with CLL) and the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas (Cheson et al, J Clin Oncol 2007 for pts with SLL). Results: To date, 30 CLL/SLL patients (including 4 treatment-naive) have been enrolled across the 2 studies. Eighty-four percent of subjects are men with an overall median age of 68 (range 44–82) years. Of the subjects with prior therapy for CLL/SLL the median number of prior therapies is 3 (range 1–4). Treatment has been well-tolerated; Grade ≥ 3 toxicities have been infrequent (10/30 pts; 33%). Two study-drug related serious adverse events have been reported: 1 case of viral adenitis (Grade 3) and 1 case of viral infection (Grade 2). Two adverse events have led to discontinuation of study drug: a small bowel obstruction (Grade 3) and exacerbation of chronic obstructive disease (Grade 3); both events were reported as unrelated to study drug. No study-drug related deaths have reported. There has been no change in either NK cell or T cell counts. Target inhibition as measured by a probe of Btk drug occupancy showed inhibition of Btk at PCI-32765 exposure levels of ≥ 245 ng•h/mL. Of the 14 patients currently evaluable for response using the pre-defined criteria, the overall response rate is 64% (1 complete remission [CR], 8 partial remissions [PR], and 4 SD). Both studies are ongoing and open to enrollment. An update on response rate, response duration, safety, and PD information will be presented on enrolled patients based on a November 2010 database cut-off. Conclusion: PCI-32765 is a novel oral and selective “first-in-human” inhibitor of Btk that induces objective partial and complete responses in a substantial proportion of pts with CLL/SLL and has a favorable safety profile. These data support further studies of both monotherapy and also combination treatment with PCI-32765 in CLL/SLL. Disclosures: O'Brien: Pharmacyclics, Inc: Honoraria, PI grant. Fowler:Pharmacyclics: Consultancy, Research Funding. Advani:Pharmacyclics, Inc: Honoraria, PI grant. Sharman:Pharmacyclics, Inc: Honoraria, PI grant. Furman:Pharmacyclics, Inc: PI grant. Izumi:Pharmacyclics, Inc: Employment. Buggy:Pharmacyclics, Inc: Employment, Equity Ownership. Loury:Pharmacyclics: Employment, Equity Ownership. Hamdy:Pharmacyclics, Inc: Employment, Equity Ownership.

Interim results of a phase 1/2 study of JNJ-63723283, an anti-PD-1 monoclonal antibody, in patients with advanced cancers.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 58-58 ◽  
Author(s):  
Emiliano Calvo ◽  
Victor Moreno ◽  
Enriqueta Felip ◽  
Giuseppe Curigliano ◽  
Daniel Morgensztern ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
Pleural Effusion ◽  
Phase 1 ◽  
Study Drug ◽  
Clinical Activity ◽  
Phase 2 ◽  
Duration Of Treatment ◽  
Safety And Efficacy ◽  
Grade 3

58 Background: JNJ-63723283 (JNJ-283), an anti-programmed cell death protein-1 antibody, enhances T cell-mediated cytokine induction and reduces tumor volume in preclinical models. A phase 1/2 study is ongoing to evaluate the safety and efficacy of JNJ-283 in patients (pts) with advanced cancers. Methods: Eligible pts have advanced or refractory solid tumor malignancies. Phase 1 dose escalation starting from 80 mg Q2W was supported by a modified continual reassessment method to identify the recommended phase 2 dose(s) (RP2D). Safety and efficacy of the RP2D(s) will be evaluated in phase 2. Pharmacokinetics (PK), receptor occupancy (RO) and other pharmacodynamic parameters were assessed. Results: As of data cut-off, 32 pts were treated with JNJ-283 80 mg (n = 4), 240 mg (n = 16) or 460 mg (n = 4) Q2W, or 480 mg (n = 8) Q4W; 16 pts remain on study drug. Median duration of treatment was 58 days (range 16 – 240). Median age was 56 years (range 27 - 80) and median prior lines of therapy was 3 (range 1 - 12). One dose-limiting toxicity of grade 3 pleural effusion was reported at 240 mg Q2W. An RP2D of 240 mg Q2W is being evaluated in phase 2. Most common adverse events (AEs) were anemia (28.1%), hypertension (28.1%), diarrhea (21.9%) and hyponatremia (21.9%). Observed serious AEs were pleural effusion, pneumonia and chest pain (6.3% each). Infusion-related AEs of nausea and rash occurred in 6.3% of pts each. Immune-related AEs (irAEs) were reported in 21.8% of pts and were mostly grade 1-2; grade 3 irAEs included pleural effusion, pneumonitis, AST increased and ALT increased. One pt discontinued treatment due to a treatment-related AE. Three pts achieved a partial response at 240 mg Q2W; 18 pts achieved stable disease or better. Preliminary serum JNJ-283 concentrations demonstrated linear PK with dose-proportional increases and interpatient variability generally consistent with monoclonal antibody therapeutics. Preliminary circulating T cell RO demonstrated dose-independent saturation. Conclusions: JNJ-283 displayed a well-tolerated safety profile with preliminary antitumor activity in pts with advanced cancers. The trial is ongoing to further characterize the safety, PK and clinical activity of JNJ-283. Clinical trial information: 2016-002017-22.

scholarly journals A Phase 1/2, Dose and Schedule Evaluation Study to Investigate the Safety and Clinical Activity of Belantamab Mafodotin Administered in Combination with Lenalidomide and Dexamethasone in Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2736-2736
Author(s):  
Evangelos Terpos ◽  
Maria Gavriatopoulou ◽  
Ioannis Ntanasis-Stathopoulos ◽  
Panagiotis Malandrakis ◽  
Despina Fotiou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Event ◽  
Research Funding ◽  
Phase 1 ◽  
Safety Analysis ◽  
Health Data ◽  
Clinical Activity ◽  
Newly Diagnosed ◽  
Treatment Naïve ◽  
Grade 3

Abstract Background: The combination of lenalidomide with dexamethasone (Rd) represents a preferred treatment backbone for newly diagnosed, transplant-ineligible patients (pts) with multiple myeloma (MM), while the addition of a third drug (i.e., daratumumab, bortezomib, carfilzomib or ixazomib) leads to higher response rates and deeper responses. Belantamab mafodotin (belamaf; GSK2857916) is a multi-modal antibody-drug conjugate that has demonstrated a clinically meaningful anti-myeloma activity with a manageable safety profile in heavily pre-treated pts with relapsed or refractory MM. Preclinical evidence suggest a potential synergy between belamaf and lenalidomide; at the same time, these drugs do not have overlapping toxicities. Thus, there is strong rationale for investigating the clinical activity of upfront belamaf in combination with Rd in transplant-ineligible MM pts. Aims: The present analysis evaluates the safety profile of belamaf in 3 different dosing schemes in combination with Rd in treatment-naïve, transplant-ineligible MM pts. Methods: BelaRd (study short title) is an open-label, single-center, phase 1/2 study conducted in Greece, aiming to enroll 66 newly diagnosed, transplant-ineligible MM pts. The study comprises 2 parts. Part 1 will evaluate 3 doses of belamaf (2.5, 1.9, and 1.4 mg/kg) in combination with Rd, each given in an individual cohort of pts, and will determine the recommended phase 2 dose (RP2D). In this part, belamaf will be administered q8w and, depending on toxicity, dosing may be rescheduled to q4w or q12w. In Part 2, a single cohort of pts will be treated with belamaf in the RP2D in combination with Rd to further evaluate the safety and clinical activity of this regimen. Part 2 will also evaluate 2 different sets of guidelines for ocular adverse events (AEs) in 2 separate groups of pts to identify the optimal method for the management of belamaf-related keratopathy. This is the initial safety analysis of Part 1 and includes pts who received ≥1 belamaf dose and were followed up for ≥8 weeks. Results: Overall, as of 16 July 2021 (cut-off date), 18 pts completed the dose-limiting toxicity (DLT) observation period, defined as specific ≥ grade 3 AEs occurring during the first cycle of study treatment, and were included in the safety analysis. The median age was 72 years (range: 65-82), and the majority of pts were male (55.6%). Lytic bone lesions were present in 12 (66.7%) pts; no pts had extramedullary disease. Most pts (9, 50.0%) had Eastern Cooperative Oncology Group performance status 0 followed by those at 1 (8, 44.4%) and 2 (1, 5.6%). Regarding the revised International Staging System, most pts (13, 72.2%) were at stage II, followed by those at stages III (2, 11.1%) and I (3, 16.7%); 3 (16.7%) pts had high-risk cytogenetics, defined as del17p13, t(4;14) or t(14;16). By the cut-off date, pts had received a median of 4 treatment cycles, with 17 (94.4%) pts still being on treatment; 1 (5.6%) pt died due to pneumonia, unrelated to the study treatment. 16 (88.9%) pts experienced ≥1 treatment emergent adverse event (TEAE). In total, 11 (61.1%) pts had ≥1 TEAE grade 3/4, of which 1 was related to belamaf; 1 (5.6%) pt experienced a serious adverse event (SAE). There were 2 cases of dose reduction and 1 case of dose delay. The most common grade 3/4 TEAEs were fatigue (5 pts, 27.8%) and rash (4 pts, 22.7%), all related to lenalidomide. One SAE was reported: pneumonia grade 5 in the 2.5 mg/kg cohort. DLTs were noted in 3 (16.7%) pts: 1 pt with grade 3 fatigue in the 1.4 mg/kg cohort and 1 pt with grade 3 rash in each of the 1.9 and 1.4 mg/kg cohorts, all related to lenalidomide. Regarding belamaf-related ocular AEs, there were 2 cases of superficial punctuate keratopathy (grade 1 and 2 each, both in the 2.5 mg/kg cohort), 10 cases of decreased visual acuity (grade 1 [8 pts, 44.4%]: 4 in the 1.9 mg/kg cohort and 4 in the 1.4 mg/kg cohort; grade 2 [2 pts, 11.1%] in the 2.5 mg/kg cohort), and 1 case of grade 1 blurred vision in 2.5 mg/kg cohort. Conclusions: In the first safety analysis of the BelaRd study no new safety signals for the belamaf-Rd combination were observed. The frequency of ocular AEs was within the anticipated range. This early analysis shows that the triplet combination can be safely administered in treatment-naïve, transplant-ineligible MM pts. The enrollment in the study is ongoing, and more safety and efficacy data will become available with the inclusion of additional pts in an updated analysis. Disclosures Terpos: Novartis: Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Honoraria. Gavriatopoulou: Janssen: Honoraria; Takeda: Honoraria; Karyopharm: Honoraria; GSK: Honoraria; Genesis: Honoraria; Sanofi: Honoraria; Amgen: Honoraria. Gkolfinopoulos: Health Data Specialists: Current Employment. Manousou: Health Data Specialists: Current Employment. Dimopoulos: Janssen: Honoraria; Beigene: Honoraria; Takeda: Honoraria; BMS: Honoraria; Amgen: Honoraria.

Phase 1 dose-escalation trial using convection-enhanced delivery of radiolabeled monoclonal antibody for diffuse intrinsic pontine glioma following external radiation therapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2010-2010
Author(s):  
Mark M. Souweidane ◽  
Kim Kramer ◽  
Neeta Pandit-Taskar ◽  
Sofia Haque ◽  
Pat Zanzonico ◽  
...  
Keyword(s):  
Overall Survival ◽  
Median Overall Survival ◽  
Phase 1 ◽  
Diffuse Intrinsic Pontine Glioma ◽  
External Radiation ◽  
Pontine Glioma ◽  
Convection Enhanced Delivery ◽  
External Radiation Therapy ◽  
Grade 3 ◽  
Dose Levels

2010 Background: The prognosis of diffuse intrinsic pontine glioma (DIPG) is dire with a median overall survival less than one-year. 124I-omburtamab is a radiolabeled monoclonal antibody that targets B7-H3 epitope. We evaluated the safety of administering escalating doses and volumes of 124I-omburtamab via convection-enhanced delivery (CED) in children with DIPG. Methods: MSKCC 11-011 trial is a standard 3+3 phase 1, open-label, dose escalation study in patients with non-progressive DIPG. CED of 124I-omburtamab was performed between 4-14 weeks post-external radiation therapy. Nine dose levels of a single injection of 124I-omburtamab (Y-mAbs Therapeutics, USA) (range 0.25 to 8.0 mCi; and volume of infusion (Vi) from 250 to 8,000 µl) have been evaluated so far. Patients were assessed weekly for 30 days. Results: 46 children were evaluable for primary and secondary endpoints. The median age at enrolment was 6.5 years (range 2-17). Two patients have experienced AEs CTCAE grade 3 that were categorized as dose limiting toxicities (DLTs), which led to inclusion of three more patients at both the 4 and 6 mCi dose levels. Eight patients have reported transient AEs of grade 3 considered related to 124I-omburtamab. The acute grade 3 AEs were generally indicative of nervous system effects due to volume intolerance or radiation injury, and included hemiparesis (n = 3), dysarthria (n = 3), ataxia (n = 3), dysphagia (n = 2), muscular weakness (n = 2) and gait disturbance (n = 1). There were no related AEs CTCAE grade 4 or 5. Estimations of distribution volumes based on T2-weighted imaging were linearly related to volume with a mean volume of distribution/volume of infusion ratio (Vd/Vi) between 3 and 3.5. The mean ratio of lesion-to-whole body absorbed dose was ̃1000. Median overall survival from diagnosis across all cohorts was 14.8 months (n = 46, 95% CI 11.5, 16.8) and the survival rate estimates (with 95% confidence intervals) at 1, 2, 3 and 5 years were 0.63 (0.46;0.76); 0.13 (0.05;0.26); 0.08 (0.02;0.19); and 0.04 (0.00;0.16), respectively. Four patients have survived > 3 years; two remain alive at 46 and 96 months and two have died at 43 and 53 months, both with CNS disease outside of the treatment field and one with extra-CNS metastases. Conclusions: 124I-omburtamab via CED into the brain stem of children with DIPG and previously irradiated provides a possibility for improved treatment of DIPG. A dose of 8mCi and an infusion volume of 8,000 µl is considered safe and may provide a distribution volume large enough to cover tumor volumes up to 20 cm3. The median overall survival of all patients included in the trial appears to be increased with 3-4 months compared to historical control data from consortia trials. A phase 2 trial aiming at investigating the efficacy of radiolabeled omburtamab administered via CED is being planned. Clinical trial information: NCT01502917.

Safety and clinical activity of first-line durvalumab in advanced NSCLC: Updated results from a Phase 1/2 study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20504-e20504 ◽  
Author(s):  
Scott Joseph Antonia ◽  
Julie R. Brahmer ◽  
Ani Sarkis Balmanoukian ◽  
Dong-Wan Kim ◽  
Sang-We Kim ◽  
...  
Keyword(s):  
Safety Profile ◽  
Phase 1 ◽  
Single Agent ◽  
Safety Data ◽  
Clinical Activity ◽  
First Line ◽  
Tumor Biopsy ◽  
Treatment Naïve ◽  
Grade 3 ◽  
Ecog Ps

e20504 Background: Single-agent durvalumab demonstrated manageable safety and encouraging clinical activity in advanced squamous and non-squamous NSCLC in preliminary analyses from the Phase 1/2 1108 study (NCT01693562). Here we present updated safety data and clinical activity in NSCLC pts with no prior treatment for advanced disease. Methods: In this Phase 1/2 dose-escalation and expansion study, pts with Stage IIIB/IV NSCLC, ECOG PS 0–1, and availability of a fresh tumor biopsy and/or archival tumor tissue for PD-L1 testing received durvalumab 10 mg/kg every 2 weeks for up to 12 months, with retreatment permitted for those progressing after 12 months of therapy. Tumor PD-L1 expression was assessed using the Ventana PD-L1 (SP263) Assay (PD-L1 high: ≥25% of tumor cells with membrane staining). Results: As of 24 October 2016, 59 pts (63% ECOG PS 1, 49% squamous) received first-line durvalumab. Median duration of follow-up was 17.3 (1.0–36.8) mos. Safety profile was consistent with the overall (N = 304, ≥0 prior lines of therapy) NSCLC cohort. All-grade treatment-related adverse events (AEs) were reported in 56%; the most common were fatigue (15%), diarrhea (13%), and decreased appetite (10%). 7% had a treatment-related AE leading to discontinuation of durvalumab, including diarrhea in 2 pts. Grade ≥3 treatment-related AEs (all n = 1) occurred in 10%; 1 pt died due to drug-related pneumonia. 49 pts had high PD-L1 expression and 9 pts had low/negative PD-L1 expression; data are not summarized for the latter group due to the small number of pts. For the PD-L1 high subpopulation, confirmed ORR (investigator-assessed RECIST v1.1) was 28.6% (95% CI 16.6–43.3) and disease control rate (stable disease ≥24 weeks) was 42.9% (95% CI 28.8–57.8); median PFS was 4.0 months (95% CI 2.3–9.1), median OS was 21.0 months (95% CI 14.5–not estimable), and 12-month OS rate was 72% (95% CI 56–83). Response rates were similar and durable regardless of histology. Conclusions: Consistent with prior data, durvalumab had a tolerable safety profile in advanced treatment-naïve NSCLC. Clinical activity was seen in PD-L1 high pts, with encouraging OS. Clinical trial information: NCT01693562.

scholarly journals EPCT-12. PNOC015: PHASE 1 STUDY OF MTX110 (AQUEOUS PANOBINOSTAT) DELIVERED BY CONVECTION ENHANCED DELIVERY (CED) IN CHILDREN WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) PREVIOUSLY TREATED WITH RADIATION THERAPY

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii306-iii306
Author(s):  
Sabine Mueller ◽  
Cassie Kline ◽  
Javier Villanueva-Meyer ◽  
Carly Hoffman ◽  
Shannon Raber ◽  
...  
Keyword(s):  
Phase 1 ◽  
Volume Ratio ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Newly Diagnosed ◽  
Convection Enhanced Delivery ◽  
Catheter Position ◽  
Pharmacodynamic Effects ◽  
Distribution Volume Ratio ◽  
Previously Treated ◽  
Grade 3

Abstract OBJECTIVE To determine safety and distribution of MTX110 delivered by CED in newly diagnosed DIPG patients. METHODS DIPG patients (3–21 years) were enrolled after radiation. CED of MTX110 combined with gadoteridol was completed based on dose levels (DL) (30–90 µM with volumes ranging from 3 cc (single dose) to 2 consecutive doses of 6 cc; total number of DL=7). Catheter position was chosen to maximize tumor coverage. Distribution of infusate was monitored with real-time MR imaging. Repeat CED was performed every 4–8 weeks if tolerated. Quality of life (QOL) assessments using PedsQL Generic Core and Brain Tumor modules were obtained at baseline (n=5), 3-months (n=3), and end of therapy (n=2). Single-cell RNA sequencing and analysis of histone modifications was performed to assess pharmacodynamic effects on DIPG cells. RESULTS Between May 2018-Dec 2019, 6 patients were enrolled (median age 8 years, range 5–21). Dose limiting toxicities included: grade 3 gait disturbance (DL7; cycle 1); grade 3 muscle weakness/vagus nerve disorder (DL5; cycle 4) and grade 2 intolerable dysphagia (DL7; cycle 4). Twelve CED procedures were completed at DL7 and repeated cycles ranged from 2 to 7. Infusion to distribution volume ratio was approximately 1:3.5. There were no significant changes in self-reported QOL. Parent ratings of patients’ worry (p = 0.04) and overall QOL (p = 0.03) significantly decreased at 3-months. CONCLUSION Repeat CED of MTX110 at the highest dose is tolerable. Tissue concentrations are likely to be substantially higher compared to oral dosing. Pharmacodynamic effects will be presented.

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