A Phase 1/2 Study Of Blinatumomab In Pediatric Patients With Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 70-70 ◽  
Author(s):  
Arend von Stackelberg ◽  
Gerhard Zugmaier ◽  
Rupert Handgretinger ◽  
Franco Locatelli ◽  
Carmelo Rizzari ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dose Level ◽  
Pediatric Patients ◽  
Treatment Cycle ◽  
Lymphoblastic Leukemia ◽  
Phase 1 ◽  
Cell Precursor ◽  
Equity Ownership ◽  
Grade 3 ◽  
Dose Levels

Abstract Introduction Novel approaches are needed to treat pediatric relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Blinatumomab is a bispecific T-cell engager (BiTE®) antibody that has shown remission in an exploratory study of 36 adult patients with relapsed/refractory ALL. Primary toxicities in adults have been cytokine release syndrome (CRS) and central nervous system (CNS) related toxicity. We initiated a phase 1/2 multicenter study to identify, in the phase 1 part, the optimal dose of blinatumomab in pediatric patients with relapsed/refractory BCP-ALL. Methods In this ongoing study, eligible patients are <18 years old and must have BCP-ALL that is refractory, in second or later bone marrow relapse, or in any marrow relapse after allogeneic hematopoietic stem cell transplantation (HSCT). Blinatumomab is administered by continuous intravenous infusion over 28 days, followed by a 14-day treatment-free interval (up to five cycles). Data from the five doses that have been explored to date are presented. Maximum tolerated dose (MTD), defined as the highest dose level with less than two of six patients experiencing dose-limiting toxicity (DLT) within the first treatment cycle, is the primary endpoint in the phase 1 part of the study (rolling 6 design). Serum samples were collected for pharmacokinetics evaluation and cytokine measurement. Results In the phase 1 part of the study, 34 patients received a total of 56 cycles. Six (18%) patients had refractory disease and 6 (18%) had experienced at least two bone marrow relapses. Twenty-two (65%) patients had relapsed following HSCT. DLTs for dose levels 1 through 4 are summarized in the Table. The MTD for this patient population was established at 15 µg/m²/day. In order to reduce the risk of CRS, a dose of 5 µg/m²/day for 7 days escalating to 15 µg/m²/day for the remainder of the first cycle and all following cycles (5→15 µg/m²/day; dose level 5) was evaluated as recommended dose. None of the 11 patients treated at this dose level developed CRS and no grade 3 CNS-related adverse events (AEs) occurred. Across dose levels, the most common AEs regardless of causality were pyrexia (62% of patients), headache (35%), anemia (29%), and hypertension (29%). One patient treated at 5 µg/m²/day had a grade 3 seizure at the beginning of the second treatment cycle, which resolved clinically and showed no changes on MRI. Across all dose levels, 11 (32%) patients had complete remission (CR), one (3%) had hypocellular blast-free bone marrow, and two (6%) had partial remission within the first two treatment cycles, for an overall response rate of 41%. Some efficacy assessments are still ongoing, and full response data for the phase 1 part of the study will be available at the time of presentation. Two patients experienced hematologic relapse (one each at dose levels 2 and 3, during the fifth and third cycles, respectively). Pharmacokinetic parameters, such as steady-state concentration (Css) and clearance, appeared to be similar to those from adult patients with relapsed/refractory BCP-ALL who received body surface area-based blinatumomab dosing. Transient elevations of serum cytokines were observed mainly in the first two days after infusion start, in particular IL-6, IFN-gamma, IL-10, and, to a lesser extent, IL-2 and TNF-α. Conclusions In the ongoing phase 1 part of this study in pediatric patients with relapsed/refractory BCP-ALL, a dose of 15 µg/m²/day was established as MTD. Cytokine-release syndrome has been dose-limiting. Pharmacokinetic analysis at the recommended dose of 5→15 µg/m²/day is ongoing. This dose de-escalation strategy has been successful in ameliorating severe CRS to date. Blinatumomab treatment has shown promising antitumor activity in this relapsed/refractory patient population. Disclosures: von Stackelberg: Amgen Inc.: Honoraria. Zugmaier:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Rheingold:Novartis: Research Funding. Holland:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership. Mergen:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Fischer:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Zhu:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership. Hijazi:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Gore:Amgen Inc.: Travel expenses paid for DSMC meeting (Feb 2013) Other.

Initial Results from a Phase 2 Study of Blinatumomab in Pediatric Patients with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3703-3703 ◽  
Author(s):  
Lia Gore ◽  
Franco Locatelli ◽  
Gerhard Zugmaier ◽  
Christian M. Zwaan ◽  
Deepa Bhojwani ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Phase 1 ◽  
Phase 2 ◽  
Off Label Use ◽  
Cell Precursor ◽  
Off Label ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Acute lymphoblastic leukemia (ALL) is the most common malignant disease in childhood. Patients (pts) with relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) and/or multiple prior salvage therapies and/or refractory disease have a particularly poor prognosis. Blinatumomab is an investigational bispecific T-cell engager (BiTE®) antibody construct that redirects T cells to CD19+ B cells resulting in serial lysis. In phase 2 clinical studies, blinatumomab has demonstrated antitumor activity in adults with relapsed/refractory non-Hodgkin lymphoma and ALL. We evaluated efficacy and toxicity of blinatumomab in pediatric pts with relapsed/refractory ALL who have a particularly poor prognosis. Methods: Eligible pts were 2-18 years of age and had B-cell precursor ALL that was refractory, in ≥2nd bone marrow relapse, or in any marrow relapse after alloHSCT. This was a multicenter, open-label study using a Simon 2-stage design with a phase 1 and a phase 2 part. In the phase 1 part, a stepwise dose of 5→15 µg/m²/day was established as the recommended phase 2 dose (von Stackelberg et al. Blood. 2013;122:70). Blinatumomab was given by continuous intravenous infusion for 4 weeks (5 µg/m²/day for the first week and 15 µg/m²/day thereafter), followed by two treatment-free weeks (one cycle) for up to five cycles. The primary endpoint for the phase 2 part of the study was rate of complete remission (CR) within the first two cycles of treatment, including CR with incomplete hematologic recovery. Secondary endpoints included relapse-free survival (RFS), rate of advancement to alloHSCT, overall survival (OS), and incidence and severity of adverse events (AEs). Minimal residual disease (MRD) response (<10-4 leukemic cells by PCR or flow cytometry) was an exploratory endpoint. We present 39 pts who were treated at the phase 2 dose (5→15 µg/m²/day), including 18 pts from the dose expansion cohort of the phase 1 part and 21 pts from the phase 2 part of the study. Results: 39 pts received blinatumomab at a dose of 5→15 µg/m²/day. The median (range) age was 9 (2–16) years; 62% of pts were male. Sixteen (41%) pts had one and 16 (41%) pts had two or more prior salvage therapies, respectively; seven (18%) were either primary refractory or had refractory relapse. Twenty-five (64%) pts had received prior alloHSCT; of those, six (16%) had one relapse and 19 (50%) had two or more relapses. Of the 39 pts, 34 (87%) had relapsed within 6 months prior to study entry. The median (range) time from last prior relapse to the relapse at study entry was 2.1 (0–13.7) months. 69% of pts had bone marrow blast infiltration of ≥50%. 19 (49%) pts started and completed one cycle of blinatumomab treatment (two cycles, 4 [10%] pts; three cycles, 2 [5%] pts). During the first two treatment cycles, 12 pts achieved CR, (31%; 95% CI, 17%–48%), mainly during the first cycle. Two additional pts (5%) had blast-free hypoplastic or aplastic bone marrow. Among pts with CR in the first two cycles, five (42%) had complete MRD response. Median RFS for CR responders was 5.6 (95% CI, 2.6–12.1) months. Among all 39 pts, median OS was 4.3 (95% CI, 3.6–8.1) months with 6 months of study follow-up time. Six (50%) of the 12 pts with CR proceeded to alloHSCT. An additional five pts who did not respond to blinatumomab received alloHSCT after blinatumomab treatment was stopped. All pts experienced AEs, mostly flu-like symptoms consistent with the mechanism of action of blinatumomab. AEs regardless of causality occurring in >20% of pts were pyrexia (74%), anemia (33%), nausea (31%), headache (28%), hypertension (26%), increased alanine aminotransferase (23%), and cough (21%). The most common grade ≥3 AEs included anemia (26%), pyrexia (21%), increased alanine aminotransferase (18%), increased aspartate aminotransferase (18%), and febrile neutropenia (15%). Cytokine-release syndrome occurred in three (8%) pts, two of whom (5%) had grade 3 events. Conclusions: Blinatumomab showed promising antileukemia activity in heavily pretreated pediatric relapsed/refractory B-cell precursor ALL pts, with a median time from last relapse of 2.1 months. Half of the pts who responded within the first two cycles were able to receive alloHSCT following blinatumomab-induced remission, suggesting that blinatumomab may open a window for alloHSCT in those pts who are resistant to salvage chemotherapy. Disclosures Gore: Amgen Inc.: Travel Support Other. Off Label Use: This presentation will discuss the off-label use of blinatumomab, as this agent is not approved for use by the FDA, EMA or any other regulatory authorities.. Zugmaier:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Hu:Amgen Inc.: Employment, Equity Ownership. Mergen:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Fischer:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. von Stackelberg:Amgen Inc.: Consultancy, Honoraria.

scholarly journals Updated Phase 1 Results of Zuma-3: Kte-C19, an Anti-CD19 Chimeric Antigen Receptor T Cell Therapy, in Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 897-897 ◽  
Author(s):  
William G. Wierda ◽  
Michael R. Bishop ◽  
Olalekan O. Oluwole ◽  
Aaron C. Logan ◽  
Maria R. Baer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Median Time ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Phase 1 ◽  
Adult Patients ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3 ◽  
Time To Onset

Abstract Background: Although approximately half of adult patients with acute lymphoblastic leukemia (ALL) achieve long-term survival, those who relapse have poor long-term outcomes (El Fakih et al. Hematol Oncol Stem Cell Ther. 2017; Oriol et al. Haematologica. 2010). The initial report of Phase 1 of ZUMA-3, the Phase 1/2 trial of KTE-C19 for treatment of relapsed/refractory (R/R) ALL (NCT02614066), has thus far demonstrated promising efficacy among patients infused with KTE-C19, with a 71% complete remission (CR) rate (CR or CR with incomplete hematologic recovery [CRi]), 88% undetectable minimal residual disease (MRD), and manageable toxicity across all doses (Shah et al. ASH 2017. #888). Here, we present updated safety and efficacy data from Phase 1 of ZUMA-3. Methods: Adult patients (≥ 18 y) with R/R ALL (Ph+ allowed), > 5% bone marrow blasts, and ECOG 0-1 received 2, 1, or 0.5 × 106 CAR T cells/kg after low-dose conditioning chemotherapy with fludarabine 25 mg/m2/day for 3 days and a single dose of cyclophosphamide 900 mg/m2 on the third day of conditioning. The primary endpoint for Phase 1 was incidence of dose-limiting toxicities (DLTs). Key secondary endpoints included incidence and time to onset and resolution of adverse events (AEs), rate of undetectable MRD remission in the bone marrow using flow cytometry, and duration of remission. KTE-C19 expansion and persistence were also assessed. Safety analyses included all patients who received KTE-C19, and patients with ≥ 2 months of follow-up were evaluated for efficacy. Results: As of April 12, 2018, 35 patients have received KTE-C19 with a median follow-up of 11 months (range, 2 - 25 months). The median age was 40 years (range, 18 - 69 years), 51% of patients were male, 66% had ECOG 1, 13 patients (37%) had prior blinatumomab, and 60% had received ≥ 3 prior lines of treatment. The median bone marrow blast burden at screening was 70% (range, 5 - 100). Six patients received the 2 × 106 cells/kg dose, 14 received 1 × 106 cells/kg, and 15 received 0.5 × 106 cells/kg. No DLTs were observed in the DLT period. The most common Grade ≥ 3 AEs were hypotension (40%), pyrexia (34%), decreased platelet counts (34%), and anemia (31%). Grade ≥ 3 CRS occurred in 9 patients (26%), with a median time to onset of 5 days (range, 1 - 15 days). There were 2 KTE-C19-related Grade 5 events: 1 cerebral infarction at the 0.5 × 106 cells/kg dose and 1 previously reported multiorgan failure secondary to cytokine release syndrome (CRS) at the 2 × 106 cells/kg dose. Grade ≥ 3 CRS resolved in all patients (not including 2 patients with a Grade 5 event), and the median time to resolution was 11 days (range, 7 - 42 days). Grade ≥ 3 treatment-emergent neurologic events occurred in 16 patients (46%), and the median time to onset was 7 days (range, 4 - 24 days). With the exception of 2 patients with unresolved neurologic events due to death, Grade ≥ 3 neurologic events resolved in all patients (14/14), with a median time to resolution of 17 days (range, 6 - 53 days). Among the 32 patients evaluable for response, the overall rate of undetectable MRD was 78% (95% CI, 60% - 91%). CR or CRi was achieved by 23 patients (72%), and 1 patient (3%) had blast-free BM. KTE-C19 levels were examined in 23 patients as of July 31, 2017. Robust KTE-C19 expansion was observed across all dose levels assessed. Conclusion: High rates of remission were achieved by adult patients with R/R ALL, with approximately three-quarters of patients achieving CR or CRi with undetectable MRD after a single dose of KTE-C19 in ZUMA-3. The safety profile was generally manageable, and most cases of high-grade CRS and neurologic events resolved. These results demonstrate that KTE-C19 offers clinical benefit for patients with otherwise limited treatment options. Disclosures Wierda: AbbVie, Inc: Research Funding; Genentech: Research Funding. Bishop:United Healthcare: Employment; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Speakers Bureau; Juneau Therapeutics: Speakers Bureau; Novartis Pharmaceuticals Corporation: Speakers Bureau. Logan:Adaptive Biotech: Consultancy; Napajen: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy; Astellas: Research Funding; Pharmacyclics: Research Funding; Kite: Research Funding. Schiller:Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Research Funding. Holmes:Unum: Research Funding; Seattle Genetics: Research Funding, Speakers Bureau; Novartis: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Rigel: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy. Abedi:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau; Amgen: Research Funding; CIRM: Research Funding; BMS: Speakers Bureau; Takeda: Speakers Bureau; Gilead: Speakers Bureau; Celgene: Research Funding. Arellano:Cephalon: Research Funding. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy. Mardiros:Kite, a Gilead Company: Employment; Kite, a Gilead Company: Equity Ownership; Mustang Bio: Patents & Royalties; Kite, a Gilead Company: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Shen:Zhejiang DTRM Biopharma LLC: Other: Clinical Operations Director. Vezan:Kite Pharma: Employment; Kite, Gilead, Abbv, MRK: Equity Ownership. Jain:Kite Pharma, Amgen: Equity Ownership; Kite Pharma: Employment; Kite Pharma: Patents & Royalties.

Interim Analysis of a Phase 1 Trial of SGN-CD33A in Patients with CD33-Positive Acute Myeloid Leukemia (AML)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 623-623 ◽  
Author(s):  
Eytan M. Stein ◽  
Anthony Stein ◽  
Roland B. Walter ◽  
Amir T. Fathi ◽  
Jeffrey E. Lancet ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Phase 1 ◽  
Intensive Therapy ◽  
Employment Equity ◽  
Rapid Clearance ◽  
Equity Ownership ◽  
Grade 3 ◽  
Dose Levels ◽  
Bone Marrow Blasts

Abstract Background CD33 is expressed on the surface of myeloblasts in 85 to 90% of patients with AML and represents a promising target regardless of age, risk factors, or underlying mutational heterogeneity. SGN-CD33A is an anti-CD33 engineered cysteine antibody conjugated to an average of 2 molecules of a pyrrolobenzodiazepine (PBD) dimer, a highly potent DNA crosslinking agent. Upon binding to the cell surface, SGN-CD33A is internalized and transported to the lysosomes where PBD dimer is released within the cell through proteolytic cleavage of the linker, crosslinking DNA and leading to cell death. Methods This phase 1, open-label, 3+3 dose-escalation study (NCT01902329) is designed to evaluate the safety, tolerability, pharmacokinetics (PK), and anti-leukemic activity of SGN-CD33A. Eligible patients (ECOG 0-1) must have CD33-positive AML, and have either relapsed disease following initial remission (CR) of > 3 months, or have declined conventional induction/consolidation. SGN-CD33A is administered outpatient IV every 3 weeks for up to 4 cycles (Part A), followed by optional maintenance treatment for patients achieving a CR/CRi (Part B). Investigator assessment of response is per IWG criteria (Cheson 2003). Results To date, 40 patients (48% female) with a median age of 75 years (range, 27-86) have been treated. Twenty patients had relapsed AML after 1st CR with intensive therapy (3 of these had intensive frontline therapy plus 1 additional line of low intensity therapy); 20 had declined conventional intensive therapy (13 of these patients had received 1-2 prior low intensity therapies, primarily hypomethylating agents). Of the patients enrolled, 45% had underlying myelodysplasia and most had disease with intermediate (70%) or adverse (18%) cytogenetic risk, 8% with mutated NPM1 (without FLT3 mutation) and 13% with mutated FLT3. Dose levels tested were 5 mcg/kg (n=3), 10 mcg/kg (n=3), 20 mcg/kg (n=13), 40 mcg/kg (n=18), and 60 mcg/kg (n=3). To date, a maximum of 4 cycles was received in Part A and 10 cycles in Part B (total median of 2 cycles on treatment; range, 1-13 cycles). Thirteen patients remain on treatment and enrollment is ongoing. Two dose-limiting toxicities have been reported, a Grade 3 pulmonary embolism (20 mcg/kg) and a Grade 4 hypocellular marrow (>28 days; 40 mcg/kg). The only Grade 3 or higher adverse event (AE) reported in >10% of patients was febrile neutropenia (55%). Other treatment-emergent AEs regardless of relationship to study treatment reported in ˃10% of patients were fatigue (48%), diarrhea (20%), constipation (18%), cough (18%), dyspnea (18%), epistaxis (18%), peripheral edema (18%), malaise (15%), hypokalemia (13%), and pleural effusion (13%). The 30-day mortality was 2.5%, with no treatment-related deaths occurring during that time; 1 elderly patient died from a traumatic fall unrelated to SGN-CD33A. Blast clearance in marrow was obtained in 16 of 38 efficacy evaluable patients (42%) across all dose levels. A dose-response relationship is evolving with rapid and marked decreases in bone marrow blasts at 40 and 60 mcg/kg in 19 of 21 patients (Figure 1). Of 17 efficacy evaluable patients treated at 40 mcg/kg, 8 experienced clearance of marrow blasts; these patients achieved a best clinical response of CR (2), CRi (3), and morphologic leukemia-free state (mLFS; 3) thus far. In addition, complete remissions were observed at 5 mcg/kg (1 CR), 10 mcg/kg (1 CRi), and 20 mcg/kg (2 CRis). Preliminary PK data demonstrated rapid clearance of ADC, suggesting target-mediated disposition. Plasma ADC exposure generally increased with increasing dose levels. Conclusions A MTD for SGN-CD33A is not yet identified and enrollment continues. AEs observed were generally manageable, often associated with underlying myelosuppression. To date, SGN-CD33A has demonstrated antileukemic activity with 47% achieving blast clearance at the 40 mcg/kg dose level. The observed low 30-day mortality (2.5%) and rapid clearance of marrow blasts in patients with poor risk factors (median age 75, predominantly intermediate and adverse cytogenetic risk, and 45% underlying myelodysplasia) with outpatient administration are encouraging. Enrollment is ongoing to further define optimal dose and schedule. In addition, combinations of SGN-CD33A with standard AML and MDS agents will be evaluated. Figure 1: Bone Marrow Blasts Over Time Figure 1:. Bone Marrow Blasts Over Time Disclosures Stein: Seattle Genetics, Inc.: Research Funding; Janssen Pharmaceuticals: Consultancy. Off Label Use: SGN-CD33A is an investigational agent being studied in patients with AML. SGN-CD33A is not approved for use. Stein:Seattle Genetics, Inc.: Research Funding. Walter:Seattle Genetics, Inc.: Consultancy, Research Funding; Amphivena Therapeutics, Inc.: Consultancy; Amgen: Research Funding; Amphivena Therapeutics, Inc.: Consultancy; Amgen: Research Funding. Fathi:Exelixis: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Ariad: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding. Lancet:Seattle Genetics, Inc.: Consultancy, Research Funding. Kovacsovics:Seattle Genetics, Inc.: Research Funding. Advani:Seattle Genetics, Inc.: Research Funding. DeAngelo:Seattle Genetics, Inc.: Research Funding. O'Meara:Seattle Genetics, Inc.: Employment, Equity Ownership. Zhao:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Erba:Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Seattle Genetics, Inc.: Consultancy, Research Funding.

L-Asparaginase-Loaded Red Blood Cells Combined with Standard EWALL Chemotherapy in Older Patients with Newly Diagnosed Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (Ph- ALL): First Results of the GRASPALL/GRAALL-SA2-2008 Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2579-2579
Author(s):  
Mathilde Hunault ◽  
Thibault Legay ◽  
Françoise Huguet ◽  
Stéphane Leprêtre ◽  
Eric Deconinck ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Dose Level ◽  
Blood Cells ◽  
Older Patients ◽  
Lymphoblastic Leukemia ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Equity Ownership ◽  
Grade 3 ◽  
Dose Levels

Abstract Abstract 2579 Introduction: In adults with Ph- ALL, the clinical benefit of L-asparaginase is hampered by its toxicity. With its improved efficacy/tolerability potential, L-asparaginase-loaded red blood cells (GRASPA®) could be a suitable option for combining L-asparaginase with standard chemotherapy, especially in older patients with the disease. Methods: The GRASPALL/GRAALL-SA2-2008 was an open label Phase II dose escalation study conducted by the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) in patients aged >55y with newly diagnosed ALL Ph-. The aim was to determine the optimal dose of GRASPA® that could be combined with the standard EWALL chemotherapy backbone in these patients. The primary composite endpoint included tolerance and efficacy, the latter being defined as the achievement of target asparagine depletion for at least 7 days. Hematological and molecular Ig/TCR minimal residual disease (MRD) response rates, survival and anti L-asparaginase antibody titer (Abs), were secondary endpoints. Three doses of Graspa® (50, 100 and 150 IU/kg), infused at d3 and d6 of two successive induction cycles, were investigated, using a Bayesian experimental plan. After each 3-pt cohort, an independent Data Safety Monitoring Board reviewed study drug tolerance before opening the next dose. EWALL backbone consisted of dexamethasone prephase followed by induction-1 (dexamethasone 10 mg/m2 d1-2,/8-11, vincristine 1 mg d1,8, and idarubicine 10 mg d1-2/8-9) and induction-2 (cyclophosphamide 500 mg/m2 d15-17 and cytarabine 60 mg/m2 d16-19/23-26). Consolidation consisted of 6 monthly alternating cycles with methotrexate (1 g/m2 d1), E.coli asparaginase (10,000 IU/m2 d2) and high-dose cytarabine (1 g/m2/q12 hrs d1,3,5). Maintenance included mercaptopurine, methotrexate and vincristine/dexamethasone pulses for a total duration of 2 years. Dose reductions were recommended for pts aged >70y. Results: Between March 2009 and October 2010, 30 pts were recruited in 20 GRAALL centers. The 50, 100 and 150 dose levels included 3, 13 and 14 pts, respectively. Median age was 67 years (range 59–77). Twenty-six pts had B-lineage ALL and 4 had T-ALL. No differences in baseline characteristics were observed across the 3 dose level groups. Overall, 0 (0%), 2 (15%) and 5 (36%) pts presented limiting toxicities in the 50, 100 and 150 dose level, respectively. Because of insufficient efficacy, only 3 pts received the lower 50 IU/kg dose. At the higher 100 and 150 dose levels, 85% and 71% pts reached target asparagine depletion at d7, respectively. In these two 100 and 150 IU/kg groups, grade 3/4 infections were observed in 69% and 71% pts and invasive fungal infection in 23% and 43% pts, respectively. Incidences of adverse events tended to be lower in the 100 IU/kg group: Anti L-asparaginase Abs were detected in 0/3, 2/13 and 1/14 pts after induction-1 and 1/2, 3/9 and 5/9 pts after induction-2, in the 50, 100 and 150 dose level group, respectively. Nevertheless, no clinical allergy was observed after the second drug infusion, but allergic reactions to native E-Coli L-asparaginase were observed in 5/19 pts after consolidation 1. Grade 3–4 infections and renal methotrexate toxicities were observed in 11% (11/99) and 10% (11/51) of consolidations courses. Responses to therapy were as follows: Conclusion: Two infusions of 100 IU/kg GRASPA® appear to be a safe and active manner to introduce L-asparaginase during initial induction chemotherapy of older pts with Ph- ALL. Larger prospective evaluations of this new L-asparaginase formulation are warranted. Disclosures: Liens: ERYTECH Pharma: Employment, Equity Ownership. Godfrin:ERYTECH Pharma: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

scholarly journals EPCT-02. PBTC-051: FIRST IN PEDIATRICS PHASE 1 STUDY OF CD40 AGONISTIC MONOCLONAL ANTIBODY APX005M IN PEDIATRIC SUBJECTS WITH RECURRENT/REFRACTORY BRAIN TUMORS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii304-iii304
Author(s):  
Holly Lindsay ◽  
Arzu Onar-Thomas ◽  
Mehmet Kocak ◽  
Tina Young Poussaint ◽  
Girish Dhall ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Dose Level ◽  
Pediatric Patients ◽  
Phase 1 ◽  
Pediatric Brain Tumor ◽  
Cns Tumors ◽  
Level 3 ◽  
Grade 3 ◽  
Expansion Cohort ◽  
Antigen Presenting

Abstract BACKGROUND CD40 is a co-stimulatory molecule expressed on antigen presenting cells (APCs). APX005M is a CD40 agonist monoclonal antibody which stimulates innate and adaptive anti-tumor immunity through activation of APCs, macrophages, and antigen-specific CD8+T-cells. Pediatric Brain Tumor Consortium study PBTC-051 is the first investigation of APX005M in pediatric patients and is evaluating the safety, recommended phase 2 dose (RP2D), pharmacokinetics, and preliminary efficacy of APX005M in children with central nervous system (CNS) tumors. RESULTS Accrual of patients with recurrent/refractory primary malignant CNS tumors (stratum 1) began in March 2018. 16 patients (2 ineligible) have enrolled on this stratum; 14 were treated. Dose escalation through 3 planned dose levels of APX005M was completed without excessive or unanticipated toxicities. The highest dose level (0.6 mg/kg q3 weeks) is the presumptive RP2D, and an expansion cohort is currently enrolling at this dose. 2 patients at dose level 3 have received &gt;12 cycles of therapy. Grade 3 or higher adverse events at least possibly attributable to APX005M include 11 lymphopenia, 5 neutropenia, 5 leukopenia, 3 ALT elevations, 1 AST elevation, 1 thrombocytopenia, and 1 hypoalbuminemia. PK data will be available March 2020. Stratum 2 is now enrolling patients with post-radiation/pre-progression DIPG beginning at dose level 2, with 1 patient currently enrolled. CONCLUSION The CD40 agonistic antibody APX005M has demonstrated preliminary safety in pediatric patients with recurrent/refractory primary malignant CNS tumors and has a likely RP2D of 0.6 mg/kg q3 weeks in this population. Preliminary efficacy data are pending.

Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia

Blood ◽  
2004 ◽  
Vol 103 (3) ◽  
pp. 784-789 ◽  
Author(s):  
Sima Jeha ◽  
Varsha Gandhi ◽  
Ka Wah Chan ◽  
Lisa McDonald ◽  
Irma Ramirez ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Nucleoside Analog ◽  
Dismal Prognosis ◽  
Heavily Pretreated ◽  
Inhibition Of Dna Synthesis ◽  
Dose Levels ◽  
Sustained Inhibition

Abstract Despite progress in leukemia therapy, most children who experience relapse have a dismal prognosis. New, effective approaches are needed. We conducted a phase 1 study of a novel nucleoside analog, clofarabine, in pediatric patients with refractory and relapsed leukemia. Clofarabine was infused intravenously over 1 hour each day for 5 days. Six dose levels, between 11.25 and 70 mg/m2 per day for 5 days, were studied in 25 patients. A modified 3 + 3 phase 1 design was followed with 30% dose escalation until the dose-limiting toxicity (DLT) was defined. The maximum tolerated dose (MTD) was 52 mg/m2 per day for 5 days. At the end of infusion at MTD, clofarabine triphosphate levels in leukemia blasts varied between 6 μM and 19 μM, which resulted in complete and sustained inhibition of DNA synthesis. The DLT was reversible hepatotoxicity and skin rash at 70 mg/m2 per day for 5 days. Twenty-five patients were treated. Five patients achieved complete remission (CR), and 3 achieved partial remission (PR), for an overall response rate of 32%. Clofarabine is well tolerated and shows significant antileukemic activity in heavily pretreated children. Multicenter phase 2 trials in pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are ongoing.

Clinical Safety and Activity In a Phase 1 Study of CAL-101, An Isoform-Selective Inhibitor of Phosphatidylinositol 3-Kinase P110δ, In Patients with Relapsed or Refractory Non-Hodgkin Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1777-1777 ◽  
Author(s):  
Brad Kahl ◽  
John C. Byrd ◽  
Ian W. Flinn ◽  
Nina Wagner-Johnston ◽  
Stephen Spurgeon ◽  
...  
Keyword(s):  
Clinical Research ◽  
Research Funding ◽  
Phase 1 ◽  
Selective Inhibitor ◽  
Phase 1 Study ◽  
Non Hodgkin Lymphoma ◽  
Duration Of Response ◽  
Equity Ownership ◽  
Grade 3 ◽  
Dose Levels

Abstract Abstract 1777 Introduction: The class I phosphatidylinositol 3-kinases (PI3Ks) regulate cellular functions relevant to oncogenesis. Expression of the PI3K p110δ isoform (PI3Kδ) is restricted to cells of hematopoietic origin where it plays a key role in B-cell proliferation and survival. In non-Hodgkin lymphoma (NHL) cells, constitutive PI3Kδ-dependent PI3K pathway activation is frequently observed. CAL-101 is an isoform-selective inhibitor of PI3Kδ that inhibits PI3K signaling and induces apoptosis of NHL cell lines in vitro. Methods and Patients: This Phase 1 study evaluated the safety, pharmacokinetics and activity of orally administered CAL-101 in patients with relapsed or refractory hematologic malignancies. Sequential cohorts of patients were enrolled at progressively higher dose levels with cohort expansion based on toxicity profile and plasma exposure. CAL-101 was administered orally once or 2 times per day (QD or BID) continuously in 28-day cycles for up to 12 cycles (with the potential for more prolonged therapy on an extension protocol thereafter). Tumor response was evaluated based on standard criteria but without a requirement for PET imaging. Results: At data cutoff, the study had enrolled 55 patients with NHL; 28 patients had indolent NHL (follicular lymphoma n=15, small lymphocytic lymphoma n=6, Waldenstrom's macroglobulinemia n=4, marginal zone lymphoma n=3) and 27 had aggressive NHL (mantle cell lymphoma [MCL] n=18, diffuse large B-cell lymphoma [DLBCL] n=9). Patient characteristics included 69% males (38 vs 17 females), median age [range] of 68 [32-82] years, 44% with refractory disease and 56% with relapsed disease. The median [range] number of prior therapies was 5 [1-12]. The proportion of patients with specific prior therapies included: indolent NHL-rituximab 96%, alkylator 86%, anthracycline 50%, purine analog 36%; aggressive NHL-rituximab 100%, alkylator 100%, anthracycline/anthracenedione 96%, plus bortezomib 72% in MCL patients. CAL-101 dose levels were 50 mg BID (n=2), 100 mg BID (n=11), 150 mg BID (n=8), 200 mg BID (n=16), 350 mg BID (n=9) and 300 mg QD (n=9). The median [range] number of treatment cycles was 4 [1-16], with 16 (29%) patients continuing on treatment (11 on study and 5 on the extension protocol after 12 cycles). Symptomatic adverse events were infrequent, usually low-grade, and not clearly CAL-101-related. Grade ≥3 hematological laboratory abnormalities included neutropenia n= 5 (9%), lymphopenia n=3 (5%), and thrombocytopenia n=3 (5%) with uncertain relationship to CAL-101. Grade≥3 ALT/AST elevations occurred in 18 (33%) patients with onset 2–8 weeks after CAL-101 initiation and resolution 2–4 weeks after CAL-101 interruption; after resolution of ALT/AST changes, most patients were rechallenged at the same or a reduced dose of CAL-101 and the majority of these patients were able to resume treatment without recurrence of transaminase elevations. Partial responses were observed at all dose levels, with respective overall n/N (response rates) in evaluable patients of 15/24 (62%) for indolent NHL, 10/16 (62%) for MCL and 0/9 (0%) for DLBCL. Respective response rates by relapsed or refractory status were 9/13 (69%) and 6/11 (55%) for indolent NHL and 8/11 (73%) and 2/5 (40%) for MCL. The median duration of response had not been reached in indolent NHL patients; 5 patients have had response durations of ≥6 months with response durations ranging to >16 months. The median [range] duration of response was 3 months [1 month to 8 months] in MCL. Pharmacodynamic data have supported drug activity; plasma concentrations of chemokines CCL22 and CCL17 were elevated at baseline and showed significant decreases within 1 cycle of CAL-101 treatment (p<0.001 for both comparisons). An evaluation of pharmacokinetics indicated minimal increases in plasma Cmax and AUC at CAL 101 doses >150 mg BID; these data, taken together with the tumor regression results, have proved helpful in supporting Phase 2–3 dose selection. Conclusions: CAL-101, an oral PI3Kδ isoform-selective inhibitor, shows acceptable safety and promising pharmacodynamic and clinical activity in patients with indolent NHL and MCL. The high rate of tumor regressions and protracted durations of tumor control in heavily pretreated patients support advancing CAL-101 into additional studies, both as a single agent and in combination with chemo/immunotherapy. Disclosures: Kahl: calistoga: Consultancy, Research Funding. Off Label Use: CAL-101 for relapsed lymphoma. Byrd:Calistoga Pharmaceutical Inc.: Equity Ownership. Flinn:calistoga: Research Funding. Wagner-Johnston:calistoga: Research Funding. Spurgeon:calistoga: Research Funding. Furman:GlaxoSmithKline: Clinical research funding, Consultancy, Research Funding, Speakers Bureau; Genentech: Clinical Research Funding, Consultancy, Research Funding, Speakers Bureau; Cephalon: Speakers Bureau, Speakers bureau; Calistoga: Consultancy, Honoraria; Celgene: Clinical Research, Consultancy, Research Funding. Brown:Genzyme: Research Funding; Celgene: Consultancy, Research Funding; Calistoga: Consultancy; Genentech: Consultancy. Coutre:calistoga: Research Funding. Lannutti:Calistoga Pharmaceutical Inc.: Employment. Ulrich:Calistoga Pharmaceuticals: Employment, Equity Ownership. Webb:Calistoga Pharmaceuticals: Employment. Peterman:Calistoga Pharmaceuticals: Employment. Holes:Calistoga Pharmaceuticals: Employment.

Phase 1/2 Trial Of Lenalidomide In Combination With Cyclophosphamide and Prednisone (REP) In Patients With Lenalidomide-Refractory Multiple Myeloma (REPEAT-study)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 287-287 ◽  
Author(s):  
Inger S. Nijhof ◽  
Sonja Zweegman ◽  
Mark-David Levin ◽  
Harry R. Koene ◽  
Aart Beeker ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Dose Level ◽  
Research Funding ◽  
Phase 1 ◽  
Oral Cyclophosphamide ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Grade 3 ◽  
Dose Levels

Abstract Background The outcome of multiple myeloma (MM) patients who are no longer responding to thalidomide, lenalidomide (LEN) and bortezomib (BORT) is very poor, with a median event-free survival of 5 months and median overall survival (OS) of 9 months (Kumar SK et al, Leukemia 2012; 26;149-157). We have previously shown in a small retrospective study that the combination of continuous low dose oral cyclophosphamide (endoxan) and prednisone combined with lenalidomide (REP) had remarkable activity in heavily pretreated LEN-refractory multiple myeloma patients (median 6 lines of previous chemotherapy) (vd Donk et al; Br J Haematol 2010;148(2):335-7). To determine the optimal dose of lenalidomide with continuous cyclophosphamide and prednisone, we initiated a prospective study to evaluate the maximum tolerated dose (MTD) of the REP regimen and to assess its efficacy and safety in LEN-refractory MM patients. Here we report safety and efficacy data from the phase 1 dose-escalation part of the REPEAT-study (NCT01352338). Patients and Methods Patients aged ≥ 18 years with LEN-refractory MM, ECOG-performance status 0-3 and adequate kidney, liver and hematologic function were included. Five dose levels were evaluated using a standard 3+3 design, based on dose-limiting toxicities (DLTs) occurring in cycle 1. Patients received LEN in doses ranging from 10-25 mg/day on days 1-21 of 28-day cycle, while oral cyclophosphamide (50 or 100 mg) and prednisone (20 mg) were given continuously. Therapy was continued until progression. The MTD for the phase 2 part is defined as the highest dose level with 0 or 1 DLT's observed in 6 patients. Results Up till now, 35 patients were enrolled (22 in phase 1 and 13 in phase 2) from August 2011 to June 2013. The phase 2 part is still recruiting and data are not evaluable yet. One patient in phase 1 was excluded because of study violation and is not included in the analysis. The median age of the 21 evaluable patients in phase 1 was 69 years (range 41-73); 76% were male. The median duration of the disease from diagnosis was 41 months (range 18-96), median number of prior therapies was 3 (range 2-6), and 12 patients (57%) had previously received autologous SCT. All patients were LEN-refractory, 19 (90%) had prior BORT treatment, and 16 (76%) had BORT-refractory MM. Fifty-five % of the patients were considered high risk by FISH. At the time of analysis, 16 of 21 patients in phase 1 have discontinued treatment because of disease progression (13), alternative treatment (allo-SCT) (1), or adverse events (2). The MTD was defined as LEN 25 mg days 1-21 of a 28-day cycle, combined with oral cyclophosphamide 50 mg and prednisone 20 mg continuously (dose level 4), based on three patients experiencing a DLT: two developed pneumonia (in dose levels 4 and 5; CTC grade 3), and one patient at dose level 5 experienced CTC grade 3 dyspnea. Neutropenia (18%) and thrombocytopenia (18%) were the most common grade 3 hematological adverse events (AEs), which were managed with growth factor support and/or dose modification. There were no grade 4 hematologic AEs. Grade 3 respiratory tract infections (29%) and grade 2 fatigue (19%) were the most common non-hematological AEs. Venous thromboembolism occurred in 1 patient. Figure 1 shows a waterfall plot of the responses of the patients that participated in the phase 1 part of the study. Overall response rate (≥ PR) was 67% with 6 out of 21 (29%) patients achieving at least VGPR. In addition 2 patients achieved MR (≥ MR: 76%). Median PFS and OS were 6.3 and 15.5 months respectively. Similar results were achieved in the subset of patients with LEN- and BORT-refractory disease. Interestingly, laboratory experiments with purified myeloma cells from these patients suggest synergism between LEN and cyclophosphamide. Conclusions The REP regimen induces high response rates and prolonged PFS and OS in LEN-refractory patients with acceptable toxicity. The MTD is defined as LEN 25 mg days 1-21 of a 28-day cycle, combined with oral cyclophosphamide 50 mg and prednisone 20 mg continuously. Phase 2 is enrolling patients and evaluates efficacy and safety of the REP regimen at the MTD. REP should be considered a valuable salvage option for LEN-refractory MM patients. We will present an updated follow-up at ASH. Disclosures: Sonneveld: Onyx: Research Funding; Millenium: Research Funding; Janssen-Cilag: Research Funding; Onyx: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Celgene: Research Funding. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria. van de Donk:Celgene: Research Funding.

A Phase I Study Of KB004, a Novel Non-Fucosylated humaneered® Antibody, Targeted Against The Receptor Tyrosine Kinase EphA3, In Advanced Hematologic Malignancies

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3838-3838 ◽  
Author(s):  
Jeffrey E Lancet ◽  
Andrew H Wei ◽  
Simon TS Durrant ◽  
Mark S. Hertzberg ◽  
Ronan T. Swords ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Phase 1 ◽  
Hematologic Malignancies ◽  
Clinical Activity ◽  
Sustained Remission ◽  
Eligibility Criteria ◽  
Bone Marrow Biopsies ◽  
Equity Ownership ◽  
Dose Levels

Abstract Background EphA3 is involved in cell positioning in fetal development. In the adult it is an oncofetal antigen re-expressed in hematologic malignancies (blood and bone marrow, leukemic stem cells) and solid tumors (tumor stem cells, neovasculature and stroma) and may be prognostic. KB004 is a humaneered® high affinity antibody targeted against EphA3 with 3 putative mechanisms of action: direct induction of apoptosis in tumor cells, activation of ADCC and disruption of tumor vasculature by induction of endothelial cell rounding and subsequent blood vessel infarction. Herein, we describe results of an ongoing, phase 1 dose-escalation study of KB004 in adult patients with advanced hematologic cancers. Objectives 1) primary: to determine safety and MTD for KB004 in patients with hematologic malignancies refractory to or unfit for chemotherapy; 2) secondary: to examine PK profile, immunogenicity, and clinical activity of KB004. Exploratory objectives include evaluation of EphA3 expression on tumor, stromal, and endothelial cells. Methods This is a multicenter phase 1 study. Key eligibility criteria include: 1) relapsed or refractory hematologic malignancy 2) ECOG PS 0-1; 3) adequate end-organ function. Additional eligibility criteria amended later to protect against hemorrhagic events, included platelets ≥ 10,000/uL (untransfused) and normal coagulation times. A standard 3 + 3 escalation study design (amended to allow up to 6 pts. per cohort in the absence of a DLT) was utilized. KB004 was administered as a 1 or 2 hr infusion on days 1, 8, and 15 of each 21-day cycle, at incremental doses of 20, 40, 70, 100, 140, 190, 250 mg and thereafter 33% increments up to a planned maximum of 700 mg. At 70 mg and above infusion reaction (IR) prophylaxis included an H1 blocker, H2 blocker, acetaminophen and IV steroids. Peripheral blood and bone marrow biopsy specimens for PK analysis and EphA3 expression, respectively, were collected during cycle 1. Results To date, 37 patients (AML 32, MDS 2, lymphoma 1, myelofibrosis 2) received KB004; 20 mg: 9 pts, 40 mg: 3pts, 70 mg: 8 pts, 100 mg: 7pts, 140 mg: 5pts, 190 mg 5pts. At 70 mg, two patients had intracranial hemorrhages 5 and 18 days after last KB004 dose in the context of thrombocytopenia and hyperleukocytosis. A causal relationship to KB004 could not be excluded. One occurred in course 1 and was considered a DLT. KB004 blood levels were near the limit of quantitation at 48 and 96 hours. Following the change to entry criteria no further episodes of serious bleeding or other DLTs or significant changes in soluble clotting factors have been observed. Overall KB004 is well tolerated. The most common toxicity was mild to moderate transient IRs in 28 (76%) patients characterized by chills, elevated temperature, fever, rigors, back pain, nausea, vomiting, hypotension, hypertension, transient hypoxia (in 2 cases). Fourteen % of infusions were slowed due to an adverse event, two (1.2%) were prematurely discontinued but no patient discontinued KB004 secondary to an IR. No other significant KB004-related toxicity has been observed. KB004 Cmax at all dose levels was above the predicted effective concentration (1 ug/ml) and was approximately dose proportional. However at dose levels below 190 mg sustained exposure to cover the entire interval between doses was not achieved. One CRp was observed at the 20mg dose level in a 78 yr-old patient with relapsed AML, who remains on study and in sustained remission for over a year. Serial bone marrow biopsies with KB004 treatment show decreased reticulin and collagen fibrosis. A > 50% reduction in marrow blast percentage was seen in 14% of AML patients, and 59% had overall stable disease beyond 1 cycle. Bone marrow biopsies positive for EphA3 expression with a cut-off of 10% of nucleated cells were obtained in 75% of AML patients. EphA3 was expressed in at least 30% of nucleated cells in the baseline sample of the patient with an ongoing CRp. Conclusion KB004 is a novel agent targeted against EphA3 that is well tolerated with evidence of clinical activity. It is anticipated that 190 mg given over 2 hours will provide sufficient plasma exposure to achieve sustained efficacy over the interval between doses. The study is ongoing. Additional PK, PD, and clinical data will be presented. Disclosures: Durrant: KaloBios: Research Funding. Yarranton:KaloBios: Employment, Equity Ownership; Glaxo: Equity Ownership; EnGen: Equity Ownership, Science Advisor, Science Advisor Other; StemLine Therapeutics: Equity Ownership. Walling:KaloBios: Consultancy; Corcept Therapeutics: Consultancy; Prothena: Consultancy; New Gen Therapeutics: Consultancy; Valent Technologies: Consultancy; LBC Pharmaceuticals: Consultancy; Amgen: Equity Ownership; BioMarin: Equity Ownership; Crown BioScience: Membership on an entity’s Board of Directors or advisory committees.

The Safety and Activity of BMS-906024, a Gamma Secretase Inhibitor (GSI) with Anti-Notch Activity, in Patients with Relapsed T-Cell Acute Lymphoblastic Leukemia (T-ALL): Initial Results of a Phase 1 Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 968-968 ◽  
Author(s):  
Patrick A. Zweidler-McKay ◽  
Daniel J. DeAngelo ◽  
Dan Douer ◽  
Hervé Dombret ◽  
Oliver G. Ottmann ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Phase 1 ◽  
Employment Equity ◽  
Mutation Status ◽  
Response Data ◽  
Notch Receptors ◽  
Equity Ownership ◽  
Grade 3 ◽  
Count Recovery

Abstract Background: Activating mutations in Notch receptors are found in multiple hematopoietic malignancies, including > 50% of patients with T-ALL, making it the most common genetic abnormality in this disease. GSIs block activation of Notch receptors and limit growth and survival in pre-clinical T-ALL models. However, various GSIs evaluated in clinical trials have had on target toxicities and have not been reported to show significant responses. CA216002 is a multicenter phase 1 trial designed to assess the safety of a novel intravenous GSI BMS-906024 in patients with relapsed or refractory T-ALL and T-cell lymphoblastic lymphoma (T-LL). We are presenting the initial toxicity profile and response data on this trial. Methods: Adults with relapsed/refractory T-ALL or T-LL were enrolled and received BMS-906024 intravenously weekly at doses of 0.6 mg, 4 mg, and 6 mg. Due to the rapid progression of T-ALL in many cases, administration of glucocorticoids or other agents was permitted and dosing guidelines for dexamethasone were provided in the protocol. Results: As of July 2, 2014, safety and response data are available on 25 patients (age 18-74 yrs) with relapsed/refractory T-ALL/T-LL that received at least one dose of BMS-906024, at doses of 0.6 mg (n=1), 4 mg (n=10), and 6 mg (n=14). Seven patients did not complete the first 4-week cycle due to rapid disease progression or disease-related death (n=5), infusion reaction (n=1), or an unrelated adverse event (n=1). Safety: The drug-related grade 3-5 adverse events included grade 4 events of anemia, hypophosphatemia, and thrombocytopenia, and grade 3 events of diarrhea, febrile bone marrow aplasia, hepatotoxicity, hypophosphatemia, pancytopenia, and tumor lysis syndrome (n=1 each). Drug-related diarrhea was common (n=11, 44%), consistent with expectations for Notch inhibition, but was generally grade 1-2 with only one grade 3 event. One dose-limiting toxicity involving grade 3 elevations of ALT and AST without bilirubin elevation (reported as grade 3 hepatotoxicity) occurred at the 4 mg dose level. One death not related to disease progression occurred, due to GI and post-surgical hemorrhage associated with pancytopenia; hemorrhage was considered not related, but pancytopenia was considered related to study drug. Responses: Eight patients (32%; 4 at 4 mg and 4 at 6 mg) had at least 50% reduction in bone marrow (BM) blasts, including one formal CR and one PR (both at 6 mg), and three of these eight had 98-100% clearance of BM blasts. (One patient, marked “*” below, began the study with 0.1% BM blasts and is not included in the eight.) The patient who achieved a CR began the study with 85% BM blasts and an absolute peripheral blood (PB) blast count of 38 k/mcL. By the end of the first cycle the BM and PB were cleared of blasts, and by the end of the second cycle there was count recovery. This patient received dexamethasone during the first cycle only, and left the study after 3 cycles in CR for an allogeneic transplant. The patient who achieved a PR began with 32% BM blasts, and by the end of the first cycle the BM blasts had decreased to 7% with improvement in ANC. The additional six patients with 50-100% decreases in BM blasts had residual lymphadenopathy, had incomplete count recovery or failed to meet other criteria which prevented them from being considered CR or PR based on the protocol definitions. One of these six patients also received hydroxyurea beginning on study day 16. Biomarkers: The figure shows change in BM blasts in 12 patients with paired BM assessments and Notch mutation status available. BM responses occurred in both Notch mutant and wildtype patients. Conclusions: Overall 8 of the 25 patients (32%) showed at least 50% reduction in BM blasts including one CR and one PR. Although the contribution of concurrent glucocorticoid therapy to the improvement in some patients is not clearly defined, the multiple responses on this trial suggest anti-leukemia activity of BMS-906024. This represents the first Notch targeting trial leading to multiple responses in relapsed/refractory T-ALL. BMS-906024 was relatively well tolerated, with minimal diarrhea in this population. The weekly dosing of this long-acting GSI shows promise for targeting Notch in T-ALL. Pharmacokinetic and additional biomarker data will be presented. Figure 1 Figure 1. Maximum Percent Reduction from Baseline of BM Blasts in Patients with Paired BM Assessments and Known Mutation Status Disclosures Zweidler-McKay: BMS: Research Funding. Off Label Use: BMS-906024 is in early Phase I clinical trials, and does not yet have an FDA-approved indication.. Douer:BMS: Research Funding. Ottmann:BMS: Consultancy, Honoraria, Research Funding. Vey:BMS: Honoraria. Thomas:BMS: Research Funding. Zhu:BMS: Employment. Huang:BMS: Employment, Equity Ownership. Bajaj:BMS: Employment. Fischer:BMS: Employment, Equity Ownership.

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