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

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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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

Neuro-Oncology ◽

10.1093/neuonc/noaa222.135 ◽

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

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

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2010 ◽

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.

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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)

Neuro-Oncology ◽

10.1093/neuonc/noab196.200 ◽

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.

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

Neuro-Oncology ◽

10.1093/neuonc/noab090.190 ◽

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.

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

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.7505 ◽

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]

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Lenalidomide (Revlimid), Bortezomib (Velcade) and Dexamethasone (RVD) for Heavily Pretreated Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v118.21.2936.2936 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2936-2936

Author(s):

Victor H Jimenez-Zepeda ◽

Donna E. Reece ◽

Suzanne Trudel ◽

Christine Chen ◽

Vishal Kukreti

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Research Funding ◽

Clinical Characteristics ◽

Phase 1 ◽

Prior Exposure ◽

Rank Test ◽

Continuous Variables ◽

Previously Treated ◽

Grade 3

Abstract Abstract 2936 Almost all patients (pts) with multiple myeloma eventually relapse and remission duration decreases with each regimen. The median Progression Free Survival (PFS) and Overall Survival (OS) in pts with relapsed myeloma refractory to lenalidomide (len) and bortezomib (btz) is poor at 5 and 9 months respectively. A phase 1 study of len plus btz in pts with relapsed or relapsed, refractory MM (RRMM) demonstrated favorable toxicity and promising response and survival further confirmed in a phase 2 study with len, btz and dexamethasone (dex) [RVD]. In this retrospective study, we assessed the efficacy and toxicity profile of RVD therapy for pts with advanced RRMM. We retrospectively reviewed the records of all pts with RRMM treated with RVD at Princess Margaret Hospital between 03/09 and 05/11. Relapse was defined according to the Uniform International Criteria. Pts were given RVD therapy as previous described by Anderson et al and must have completed at least one cycle of RVD therapy. Primary endpoints were response rate (RR), PFS, OS, and toxicity. Pts discontinued therapy if they experienced PD, no additional benefit or unacceptable toxicity. Definitions of response and progression were used according to the EBMT modified criteria with a category of very good partial response (VGPR). To examine variables independently prognostic for PFS and OS, multivariate Cox analysis was performed. Differences in continuous variables between groups were compared using Mann-Whitney or Kruskal-Wallis tests. Survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test. Thirty pts with RRMM received RVD therapy. Clinical characteristics are seen in Table 1. Median age at RVD initiation was 57 yrs (37–76 yrs), and 46.7% were male. Pts received a median of 3 prior therapies (1–6). In many instances, pts previously treated with len had len added to btz + dex at progression (n=6), or pts previously treated with btz had btz added to len + dex, at progression (n=5). Thalidomide (thal), len and btz containing regimens were previously used in 60%, 73.3% and 80% of pts respectively. PR or better was observed in 46.6%. After a median of 4.6 cycles (1–14), VGPR was seen in 4.8%, PR in 33% and SD in 14%. Pts who achieved PR or better experienced a significant improvement in PFS. There was no difference in terms of RR between those pts according to prior exposure to either btz or len (p=0.7 and 0.9 respectively). Eight pts experienced non-hematological grade 3/4 adverse events (26%), including muscle weakness, sepsis and pneumonia but there was no worsening of peripheral neuropathy. Grade 3–4 neutropenia and/or thrombocytopenia were commonly seen in 70% of pts (n=21). Disease progression was seen in 19 pts at a median of 3.9 months. Median PFS for pts previously exposed to len was 2.3 months vs 2.9 months for those with no prior exposure (p=0.75). On the other hand, median PFS for pts previously exposed to btz was 2.1 months vs 3.4 months for those with no prior exposure (p=0.9) In addition, median PFS for pts who achieved at least PR was significantly better at 5.9 vs 2.0 months for those who did not (p<0.005). (Figure 1) FISH cytogenetics studies were available in 19 out of 30 patients at relapse: 5 -normal, 4–13q deletion, 3-p53 deletion and 2 - t(4, 14). High-risk MM pts had a median PFS significantly lower of 0.6 months (CI 95%, 0–1.99) vs 4.7 months for those without high-risk features (CI 2.5–7.0) (p=0.008) (Figure 2) At the time of submission, 13 pts are alive (43.3%) and 7 pts (23%) continue on RVD therapy.Table 1.Clinical characteristics of patients with RRMM treated with RVDClinical characteristic N=30MedianRange%Age5737-76Male46.7%Female53.3%Hemoglobin (g/L)10571-155Creatinine (mmol/L)99.936-383Beta-2 microglobulin (mmol/L)280119-1440Lactate dehydrogenase (U/L)18189-255IgG56.6% (17)IgA23.3% (7)IgM3.3% (1)Light Chain16.6% (5)Kappa (mg/L)4005.3-346063.3% (19)Lambda (mg/L)5145.1-530036.7% (11)KappaLambda*BMPC57%6-95%M-spike serum (g/L)300-77M-spike urine (g/d)0.890-7.9Prior therapies31-6ASCT83.3% (25)Thal60% (18)Len73.3% (22)Btz80% (24)*BMPC, Bone marrow plasma cells In conclusion, RVD is active and well tolerated in pts with RRMM, including pts who have received prior len, btz, thal and ASCT but PFS is short at 3.9 months in this highly advanced disease group of patients. We question whether response is dependent on recognized risk factors such as adverse cytogenetics. Disclosures: Jimenez-Zepeda: J & J: Honoraria. Reece:Bristol, Meyers, Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Johnson&Johnson: Research Funding; Merck: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Millennium: Research Funding; Amgen: Honoraria. Kukreti:Celgene: Honoraria.

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A Phase 1/2 Study of G-CSF, Cladribine, Cytarabine, and Dose-Escalated Mitoxantrone (G-CLAM) in Adults with Newly Diagnosed Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)

Blood ◽

10.1182/blood.v128.22.1068.1068 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1068-1068 ◽

Cited By ~ 1

Author(s):

Anna B. Halpern ◽

Megan Othus ◽

Emily M Huebner ◽

Kaysey F. Orlowski ◽

Bart L. Scott ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Induction Chemotherapy ◽

Research Funding ◽

Phase 1 ◽

Hematologic Toxicity ◽

Newly Diagnosed ◽

Advisory Committees ◽

Grade 3 ◽

Dose Levels

Abstract Introduction:"7+3" with standard doses of cytarabine and an anthracycline has remained the mainstay of induction chemotherapy for newly diagnosed AML. Since some studies have shown improved outcomes with high-dose cytarabine, cladribine, or escalated doses of anthracyclines, we conducted a phase 1/2 study (NCT02044796) of G-CLAM using escalated doses of mitoxantrone for newly diagnosed AML or high-risk MDS (>10% blasts). Methods: Patients≥18 years were eligible if they had treatment-related mortality (TRM) scores of ≤6.9 (corresponding to a predicted risk of early death with standard induction chemotherapy of ≤6.9%) and adequate organ function (LVEF ≥45%, creatinine ≤2.0 mg/dL, bilirubin ≤2.5 times upper limit of normal). Excluded were patients with uncontrolled infection or concomitant illness with expected survival <1 year. In phase 1, cohorts of 6-12 patients were assigned to 1 of 4 total dose levels of mitoxantrone (12, 14, 16, or 18 mg/m2/day, days 1-3, compared to 10 mg/m2/day used in standard dose G-CLAM previously established in relapsed/refractory AML). Other drug doses were G-CSF 300 or 480 μg/day (for weight </≥76 kg; days 0-5), cladribine 5 mg/m2/day (days 1-5), and cytarabine 2 g/m2/day (days 1-5). In phase 2, patients were treated at the maximum tolerated dose (MTD) of mitoxantrone. A second identical course of G-CLAM was given if complete remission (CR) was not achieved with cycle 1. Up to 4 cycles of consolidation with G-CLA (mitoxantrone omitted) were allowed if CR or CR with incomplete platelet or blood count recovery (CRp/i) was achieved with 1-2 cycles of induction therapy. Dose-limiting toxicities (DLTs) were: 1) grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7-day delay of the subsequent treatment cycle; 2) grade ≥4 non-hematologic toxicity if recovery to grade ≤2 within 14 days, both excluding febrile neutropenia, infection or constitutional symptoms. Results: Among 33 patients (median age of 57.3 [range: 26-77], median TRM score 2.31 [0.16-5.90]) treated in phase 1, one DLT occurred at dose levels 3 and 4 (respiratory failure in both cases), establishing G-CLAM with mitoxantrone at 18 mg/m2/day as the MTD. Sixty-two patients, including 6 treated in phase 1, received G-CLAM at MTD. Patient characteristics were as follows: median age 58 (21-81) years, median TRM score 2.85 (0.06-6.73), with AML (n=52) or high-risk MDS (n=10). Cytogenetics were favorable in 6, intermediate in 44, and adverse in 12 (MRC criteria); 11 patients had NPM1 and 6 had FLT3 mutations. Fifty-two patients (83.9%, 95% confidence interval: 72.3-92.0%) achieved a CR (n=48 [77.4%: 65.0-87.1%]), or CRp/i (n=4 [6.5%: 1.8-15.7%]) with 1-2 cycles of therapy. Only 3 patients required 2 cycles to best response. Among the 48 CR patients, 43 (89.6%) were negative for measurable residual disease (MRDneg) by flow cytometry. Four patients had morphologic leukemia free state, 1 patient with myeloid sarcoma had a partial remission, 4 had resistant disease, and 1 died from indeterminate cause. One patient died within 28 days of treatment initiation (septic shock). Median times to an absolute neutrophil count ≥500/μL and a platelet count of ≥50,000/μL were 26 and 23 days. Besides infections and neutropenic fever, maculopapular rash, and hypoxia (fluid overload/infection-related) were the most common grade ≥3 adverse events. In addition to the phase 1/2 MTD cohort, there were 15 patients treated in an expansion cohort and 3 eligible patients treated off protocol with mitoxantrone at 18 mg/m2. For these 80 patients combined treated at MTD, the CR and CR/CRp/i rates were 76.3% and 81.2%. After multivariable adjustment, compared to 300 patients treated with 7+3 on the SWOG S0106 trial, G-CLAM with mitoxantrone 18mg/ m2 was associated with an increased probability of CR (odds ratio [OR]= 3.08, p=.02), CR/CRp/i (OR=2.96, p=.03), a trend towards improved MRDnegCR (OR= 3.70, p=.06), and a trend towards improved overall survival ([OS]; hazard ratio=0.34, p=.07). For the entire study cohort, the 6 and 12-month relapse-free survival were 73% (64-83%) and 62% (42-74%) and the 6 and 12-month OS were 89% (82- 96%) and 77% (67-88%). Conclusions: G-CLAM with mitoxantrone up to 18 mg/m2/day is well tolerated and has potent anti-leukemia activity. This regimen may warrant further randomized comparison with 7+3. We also plan to examine the addition of sorafenib to G-CLAM in newly diagnosed AML patients regardless of FLT3 status. Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Scott:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees. Becker:GlycoMimetics: Research Funding. Erba:Ariad: Consultancy; Gylcomimetics: Other: DSMB; Pfizer: Consultancy; Sunesis: Consultancy; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Novartis: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Speakers Bureau; Agios: Research Funding; Astellas: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celator: Research Funding; Seattle Genetics: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Amgen: Consultancy, Research Funding.

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Phase 1 single-center, dose escalation study of D2C7-IT administered intratumorally via convection-enhanced delivery for adult patients with recurrent malignant glioma.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e13532 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e13532-e13532 ◽

Cited By ~ 1

Author(s):

Dina Randazzo ◽

Annick Desjardins ◽

Vidyalakshmi Chandramohan ◽

John H. Sampson ◽

Katherine B. Peters ◽

...

Keyword(s):

Dose Level ◽

Dose Escalation ◽

Phase 1 ◽

Genetically Engineered ◽

Convection Enhanced Delivery ◽

Dose Escalation Study ◽

Who Grade ◽

Recombinant Immunotoxin ◽

Level 3 ◽

Grade 3

e13532 Background: D2C7 immunotoxin (D2C7-IT) is a dual-specific recombinant immunotoxin consisting of EGFR-wt and EGFRvIII monoclonal antibodies with a genetically engineered Pseudomonas exotoxin, PE-38KDEL. The primary objective is to determine the maximum tolerated dose of D2C7-IT when delivered intratumorally by convection enhanced delivery (CED). Methods: Inclusion criteria includes subjects with a single, recurrent supratentorial WHO grade III or IV glioma, KPS ≥ 70 and a washout of chemotherapy, bevacizumab or study drug of ≥ 4 weeks. Prior to administration of D2C7-IT, recurrent tumor must be confirmed by histopathology. A minimum of 2 subjects are accrued by dose level. Results: Currently, 23 subjects have been treated (16 male, 7 female) with a median age of 54 years. Out of 9 dose levels, 2 subjects have been treated at every dose except for 4 at dose level 3 (120 ng/ml) and 5 at dose 6 (405ng/ml). Adverse events possibly, probably or definitely related to D2C7-IT are mostly grade 1 or 2 events consisting of, but not limited to: intracranial hemorrhage (n = 1), stroke (n = 2), headache (n = 15), seizure (n = 5), confusion (n = 4), paresthesia (n = 4), dysarthria (n = 1), dysphasia (n = 4), visual disturbances (n = 7), fatigue (n = 4), gait disturbance (n = 2), elevated transaminases (n = 5), decreased platelets (n = 3), decreased neutrophil count (n = 1), nausea (n = 3), vomiting (n = 1), and thromboembolic event (n = 1). There was 1 dose limiting toxicity (grade 4 seizure at dose level 3), 2 grade 3 headaches and 1 grade 3 elevated ALT. 14 subjects are still alive with 6 remaining on study. So far, the longest survival time from infusion is 18.2+ months. Conclusions: D2C7-IT infusion via CED is safe with encouraging results. This dose escalation Phase I study is ongoing and will set the stage for the Phase II trial. Clinical trial information: NCT02303678.

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Phase 1 Trial of Cladribine, High-Dose Cytarabine, G-CSF, and Dose-Escalated Mitoxantrone (CLAG-M) Plus Gemtuzumab Ozogamicin in Adults with Newly-Diagnosed Acute Myeloid Leukemia (AML) or Other High-Grade Myeloid Neoplasm

Blood ◽

10.1182/blood-2019-126009 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3892-3892

Author(s):

Colin D. Godwin ◽

Megan Othus ◽

Mary-Elizabeth M. Percival ◽

Bart L. Scott ◽

Pamela S. Becker ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Left Ventricular Systolic Dysfunction ◽

Phase 1 ◽

Systolic Dysfunction ◽

Left Ventricular ◽

Hematologic Toxicity ◽

Newly Diagnosed ◽

Advisory Committees ◽

Grade 3

Background: We recently found that CLAG-M was safe and produced higher rates of CR/CRi and higher measurable residual disease (MRD)-negative CR (measured by multiparameter flow cytometry [MFC]) than standard "7+3" therapy in fit patients with newly-diagnosed AML or other high-grade myeloid neoplasm with ≥10% blasts (HG-MN). Since addition of the CD33 antibody-drug conjugate gemtuzumab ozogamicin (GO) to chemotherapy reduces relapse risk and improves survival in some AML patients, we conducted a phase 1 study (NCT03531918) to determine the maximum tolerated dose (MTD) of GO with CLAG-M in fit adults with newly-diagnosed AML (APL excluded) or HG-MN. Patients and Methods: Adults ≥18 years were eligible if they were fit (treatment-related mortality [TRM] score ≤13.1, corresponding to < 13.1% risk of TRM within 1 month) and had LVEF ≥45%, creatinine ≤2.0 mg/dL, and bilirubin ≤2.5-times upper limit of normal. Patients with concomitant illness with expected survival <1 year, with uncontrolled infection, or in myeloid blast phase of chronic myeloid leukemia were excluded. Doses were escalated in cohorts of 6 patients over 2 dose levels of GO ("GO1": 3 mg/m2 on day 1; "GO3": 3 mg/m2 on days 1, 4, and 7 [doses capped 4.5 mg]); the highest dose level achieved could then enroll an additional 6 patients (12 total) if ≤2 dose-limiting toxicities (DLTs) were observed. CLAG-M consisted of cladribine 5 mg/m2/day (days 1-5), cytarabine 2 g/m2/day (days 1-5), G-CSF 300 or 480 μg/day (for weight <76 kg vs. ≥76 kg; days 0-5), and mitoxantrone (18 mg/m2/day; days 1-3). A second course of CLAG-M (without GO) was given if MRD-negative CR/CRi was not achieved. DLT was defined as: 1) any grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7 day delay of the subsequent treatment cycle, with the exception of febrile neutropenia/infection; 2) any grade ≥4 non-hematologic toxicity, with the exception of febrile neutropenia/infection or constitutional symptoms, if recovery to grade ≤2 within 14 days. The protocol was approved by the Fred Hutchinson Cancer Research Center Institutional Review Board. Results: We enrolled 18 patients, median age 66 (range: 28-77) years, median TRM score 3.92 (range: 0.14-10.3) with newly-diagnosed AML (n=14) or HG-MN (n=4); 7 were "favorable", 4 "intermediate and 7 "adverse" by 2017 European LeukemiaNet criteria. The first 6 patients were treated at GO1, with 1 DLT (grade 3 left ventricular systolic dysfunction). Two subsequent cohorts of 6 were treated at GO3. Three DLTs occurred at this second dose level (grade 4 aminotransferase level increase, grade 3 posterior reversible encephalopathy syndrome, grade 3 intracranial hemorrhage). As prespecified in the protocol, with ≤4/12 DLTs the MTD was formally not reached and GO3 was declared the recommended phase 2 dose. Among 18 evaluable patients, 13 achieved CR and 2 CRi for a CR/CRi rate of 83% (95% confidence interval: 59-96%). 13/15 CR/CRi patients were negative for MRD by MFC and cytogenetics for an MRDneg CR/CRi rate of 72% (49-88%). The 3 patients without CR/CRi had marrow aplasia without MFC evidence of AML at time of study removal. Two underwent allogeneic hematopoietic cell transplantation in aplasia; the other achieved later neutrophil recovery prior to AML recurrence 2.5 months following induction without interval therapy. 5/18 did not have platelet recovery to 100,000/µL prior to the next therapy/removal from study. Median time to absolute neutrophil count of 1000/µL (achieved in 16/18 patients) and platelet count of 100,000/µL (achieved in 13/18 patients) was 35 (range: 24-48) days and 31 (range: 26-48) days, respectively. Besides infections and neutropenic fever, hypertension and left ventricular systolic dysfunction were the most common adverse events. One patient had severe, self-limited liver toxicity characterized by weight gain and elevated aminotransferases without hyperbilirubinemia and did not meet typical clinical criteria for sinusoidal obstructive syndrome. There were no deaths within 56 days of starting induction in this study cohort. Conclusions: CLAG-M with fractionated-dose GO is feasible in patients with newly-diagnosed AML/HG-MN and appears to have high anti-tumor efficacy. CR/CRi and MRDneg CR rates were similar to what we observed with CLAG-M alone (86% and 71%, respectively). A phase 2 study based on these findings has been initiated, using event-free survival as primary efficacy endpoint. Disclosures Othus: Celgene: Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Membership on an entity's Board of Directors or advisory committees. Percival:Nohla Therapeutics: Research Funding; Pfizer Inc.: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees. Scott:Agios: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Incyte: Consultancy. Becker:The France Foundation: Honoraria; Accordant Health Services/Caremark: Consultancy; AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding. Gardner:Abbvie: Speakers Bureau. Oehler:Pfizer Inc.: Research Funding; Blueprint Medicines: Consultancy; NCCN: Consultancy. Halpern:Pfizer Pharmaceuticals: Research Funding; Bayer Pharmaceuticals: Research Funding. Walter:Agios: Consultancy; Amgen: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding. OffLabel Disclosure: Cladribine is not approved for AML, only Hairy Cell Leukemia, however it is widely used for AML with literature supporting it.

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