Vadastuximab Research Articles

Beyond gemtuzumab ozogamicin: A systematic review of antibody therapies for acute myeloid leukemia.

e19006 Background: Acute myeloid leukemia (AML) is a neoplasm that is defined by the uncontrolled growth of myeloid progenitor cells. It is the most common form of acute leukemia in adults and is associated with poor outcomes in patients ≥ 75 years. Multiple antibody-drug conjugates (ADCs) are being investigating for their benefits in AML. Methods: A search was performed on PubMed, Cochrane, Scopus, Web of Science and ClinicalTrials.gov using the PRISMA guidelines. After screening 1,806 articles, a total of eight studies were included for this review. Results: Montesinos et al. gave a combination of talacotuzumab (anti-CD123 antibody) + decitabine to AML patients and reported an ORR of 27% (42/157) in the talacotuzumab + decitabine arm. Uy et al. studied flotetuzumab (anti-CD3 x anti-CD123 DART) and reported an ORR of 30% (9/30) in patients treated at the recommended phase two dose. Ho et al. noticed a CR in 26% (30/117) of patients who received a combination of vadastuximab talirine (anti-CD33 ADC) with azacytidine/decitabine. Feldman et al. observed that the ORR was higher in the lintuzumab (anti-CD33 antibody) + chemotherapy arm than control arm (36% vs 28%). Daver et al. and Vey et al. both studied lirilumab (anti-KIR antibody), but Daver et al. reported an ORR of 14% (5/32) in the lirilumab + azacytidine arm. In a separate study, Daver et al. administered nivolumab (anti-PD1 antibody) + azacytidine and noticed an ORR of 33% (23/70). Zeidan et al. reported that the durvalumab (anti-PD-L1 antibody) + azacytidine arm had a lower ORR than the control arm (31% vs 35%). A summary of the adverse events was provided below (Table). Conclusions: Antibody-based therapies are showing great promise for the treatment of AML but are associated with various adverse effects. More prospective clinical trials are needed to further assess the long-term benefits of such medications.[Table: see text]

Novel Combination Drug Regimens Using Hypomethylating Agents in Treatment of Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia

INTRODUCTION -The prognosis of acute myeloid leukemia (AML) in elderly population is inherently poor due to multiple factors including: frailty, medical co-morbidities and high treatment related morbidity with traditional induction chemotherapy and presence of adverse risk cytogenetics in 17-20% of patients. For patients who are not candidates for intensive chemotherapy, outcomes in terms of complete response/complete response with incomplete hematologic response (CR/CRi) and median overall survival (mOS) have been evaluated using hypomethylating agents(HMA) including azacytidine (AZA)(CR/CRi=18-27.8%, mOS=10.4-24.5 months) and decitabine (CR/CRi= 18-47%, mOS= 7-7.8 months). Recently, addition of venetoclax to HMA has shown to further improve CR/CRi (75%) and mOS (17.5 m). We conducted a systematic review of literature to identify recent studies that were published between 2015-2020 with an aim is to evaluate newer combination drug regimens (CDR) involving hypomethylating agents (AZA and decitabine) in treating elderly patients with newly diagnosed AML. METHODS- A comprehensive literature search was conducted in PubMed, Embase, and Cochrane databases. We included phase I/II studies that used CDR with HMA in elderly patients with newly diagnosed AML. RESULTS- Initial database search lead to 1120 studies. After exclusion (duplicates, case reports/series, relapsed/refractory AML) final analysis included 12 studies (n=655). Seven phase I/II with CDR using decitabine (n=500) were included in our review. Drugs used in combination included gemcitabine ozagamicin (n=40, CR/CRi =45%, mOS= 7 m), cladribine and low dose cytarabine (n=118, CR/CRi= 68%, mOS =13.8 m), vadastuximab talirine (n=53, CR/CRi=70%, mOS=11.3 m) and selinexor (n=5, CR/Cri= 80%) . In addition, three studies compared outcomes of CDR involving decitabine with all trans retinoic acid (ATRA)(n=93, ORR=21.9% vs 13.5%, p=0.06; mOS= 8.2 m vs 5.1 m, p=0.006) or talacotuzumab (CR/CRi= 15% vs 11%, p=0.44; mOS= 5.36 m vs 7.26 m, p=0.78) or bortezomib (CR/CRi= 39% vs 38%, p=0.91, mOS=9.3 m vs 8.9,p=0.18) to decitabine alone. In addition, cladribine and low dose cytarabine with decitabine in patients with adverse cytogenetics showed a decent CR/CRi of 50%, mOS= 10.5 months. In TP 53 positive mutations, CR/CRi was 40% and mOS was 5.4 months. Five phase I/II studies using CDR with AZA (n=155) were included in our review. Drugs included midostaurin (n= 88 , CR/CRi=25-29% mOS= 6-8 m) and pracinostat (n= 50, CR/CRi =46% mOS=19.1 m), In addition, two studies compared outcomes using CDR involving AZA with panobinostat (n=22, CR= 22.4 vs 30.8%, OS at 1 year = 60% vs 70%) or entinostat (n=18, ORR= 0% vs 16.6%, mOS=6 m vs 13 m) to AZA alone. None of the two comparative CDR studies using AZA showed superior outcome compared to AZA alone. CONCLUSIONS - Novel drug combinations involving decitabine including cladribine and low dose cytarabine, vadastuximab talarine showed superior CR/CRi and mOS compared to decitabine alone used in historic studies. In addition, CR/CRi were similar to HMA and venetoclax combination. In small number of patients, CDR with selinexor also showed superior CR/CRi compared to decitabine alone. CDR involving decitabine and ATRA showed superior mOS in direct comparison with decitabine alone. In addition, cladribine, low dose cytarabine and decitabine has shown promising outcomes in patients with adverse cytogenetics. Among CDR involving AZA only Proctinostat showed superior CR/CRi and mOS compared to historic studies with AZA alone. A recent phase III study though involving this CDR in comparison with decitabine was terminated early due to lack of efficacy on preliminary analysis. The above listed efficacious CDR involving decitabine in phase I/II studies need to be evaluated in large, randomized trials to assess for definitive benefit. If proven efficacious in larger studies, they could serve as additional first line CDR options in addition to HMA and venetoclax in treating elderly patients with newly diagnosed AML. Disclosures No relevant conflicts of interest to declare.

Overcoming Challenges in the Development of Anticancer ADCs

Overcoming Challenges in the Development of Anticancer ADCs

Orphan designation: CD33-directed antibody-drug conjugate consisting of an antibody conjugated to a DNA cross-linking pyrrolobenzodiazepine dimer drug (vadastuximab talirine), Treatment of acute myeloid leukaemia

Orphan designation: CD33-directed antibody-drug conjugate consisting of an antibody conjugated to a DNA cross-linking pyrrolobenzodiazepine dimer drug (vadastuximab talirine), Treatment of acute myeloid leukaemia

A phase 1 trial of vadastuximab talirine combined with hypomethylating agents in patients with CD33-positive AML

AbstractTreatment of acute myeloid leukemia (AML) among the elderly is challenging because of intolerance of intensive therapy and therapy-resistant biology. Hypomethylating agents (HMAs) are commonly used, with suboptimal outcomes. Vadastuximab talirine is a CD33-directed antibody conjugated to pyrrolobenzodiazepine (PBD) dimers. Preclinically, HMAs followed by vadastuximab talirine produced upregulated CD33 expression, increased DNA incorporation by PBD, and enhanced cytotoxicity. A combination cohort in a phase 1 study (NCT01902329) assessed safety, tolerability, and activity of vadastuximab talirine with HMAs. Those eligible had Eastern Cooperative Oncology Group status 0 to 1 and previously untreated CD33-positive AML, and declined intensive therapy. Vadastuximab talirine was administered intravenously at 10 μg/kg on last day of HMA (azacitidine or decitabine) infusion in 4-week cycles. Among 53 patients treated, the median age was 75 years. Patients had adverse (38%) or intermediate (62%) cytogenetic risk. Median treatment duration was 19.3 weeks. No dose-limiting toxicities were reported. The majority of adverse events were a result of myelosuppression, with some causing therapy delays. Thirty- and 60-day mortality rates were 2% and 8%, respectively. The composite remission rate (complete remission [CR] and CR with incomplete blood count recovery) was 70%. Fifty-one percent of remissions were minimal residual disease-negative by flow cytometry. Similarly high remission rates were observed in patients with secondary AML, aged at least 75 years, and with adverse cytogenetic risk. Median relapse-free survival and overall survival were 7.7 and 11.3 months, respectively. Compared with historical data for HMA monotherapy, the combination of vadastuximab talirine with HMAs produced a high remission rate, but was accompanied by increased hematologic toxicity.

Advances in targeted treatment of acute myeloid leukemia

Chemotherapy is still the main treatment of acute myeloid leukemia (AML) for the moment. The successful use of imatinib in chronic myeloid leukemia has accelerated the study of targeted therapy. With the development of next generation sequencing, researchers have a complete understanding of AML gene mutation profile. Based on that, scientists have tried to develop small molecular targeted drugs. There is no new drug for AML approved for several decades, until the United States Food and Drug Administration (FDA) approved four drugs for AML in 2017. So 2017 can be considered as the year of AML. These new drugs have been recommended in the National Comprehensive Cancer Network (NCCN) guidelines (2018) and have become the first line treatment of AML. In addition to the four approved new drugs, many drugs are in clinical trials or in preclinical stage. When more new drugs are approved in the future, the treatment of AML will truly enter the era of targeted therapy or precision therapy. This article summarizes the AML targeting drugs that have been approved and might be approved in the future, mainly including Fms-like tyrosine kinase (FLT)3 inhibitors, isocitrate dehydrogenase (IDH) inhibitors, B-cell lymphoma (BCL)2 inhibitors, immunotoxins and so on. Key words: Leukemia, myeloid, acute; Molecular targeted therapy; FLT3 inhibitors; IDH inhibitors; BCL2 inhibitors; GO; SGN-CD33A

Formation of a Novel C11-Acetone Adduct of a Pyrrolobenzodiazepine (PBD) with Loss of Cytotoxicity

The pyrrolidine-catalysed formation of novel diastereomeric C11-acetone adducts was observed during the chromatographic purification of pyrrolobenzodiazepine (PBD) compounds in the presence of acetone. The mechanism of this reaction was explored and the adducts obtained fully characterised. Talirine, the cytotoxic payload element of the antibody-drug conjugate (ADC) vadastuximab talirine, was also found to form a bis-adduct under similar conditions. A cellular cytotoxicity evaluation of the modified PBD compounds confirmed their lack of cytotoxicity, consistent with loss of the DNA-interactive N10–C11 imine functionality. As well as the new chemistry reported here, given the number of PBD-based ADCs presently in the clinic, this observation may be important for the larger-scale manufacture of PBD-based products.

A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33-positive acute myeloid leukemia

AbstractVadastuximab talirine (SGN-CD33A, 33A) is an antibody-drug conjugate consisting of pyrrolobenzodiazepine dimers linked to a monoclonal antibody targeting CD33, which is expressed in the majority of acute myeloid leukemia (AML) patients. This phase 1 study evaluated the safety, pharmacokinetics, and preliminary activity of vadastuximab talirine and determined the recommended monotherapy dose in patients with relapsed or refractory AML. Additional expansion cohorts tested vadastuximab talirine in specific subpopulations of relapsed AML, and in a cohort of older, treatment-naive patients. Patients received vadastuximab talirine IV on day 1 (5-60 µg/kg) or on days 1 and 4 (20 µg/kg) of 21-day cycles. A total of 131 patients (median age, 73 years [range, 26-89 years]) had intermediate I-II (48%) or adverse (34%) risk by European LeukemiaNet classification; 50% of patients had underlying myelodysplasia. Two dose-limiting toxicities (grade 2 pulmonary embolism and grade 4 hypocellular marrow) occurred during dose finding. Most adverse events (AEs) were consistent with myelosuppression; nonhematologic AEs included fatigue, nausea, and diarrhea. The 30-day mortality was 8%. At the recommended monotherapy dose of 40 µg/kg, the complete remission + CRi rate was 28% (5 of 18 patients); 50% of patients who responded achieved minimal residual disease negativity. In patients across dose levels who achieved CR or CRi, the median time to full count recovery was 6.4 weeks for neutrophils (≥1000/µL) and 10.6 weeks for platelets (≥100 × 109/L). Vadastuximab talirine demonstrates activity and a tolerable safety profile as a single agent in patients with AML. The recommended monotherapy dose of vadastuximab talirine is 40 µg/kg. This trial was registered at www.clinicaltrials.gov as # NCT01902329.

Abstract CT120: Assessment of myeloblast CD33 receptor occupancy (RO) by vadastuximab talirine in patients with acute myeloid leukemia (AML) receiving monotherapy treatment

Abstract Background CD33 is expressed on myeloblasts in the majority of patients with AML. Vadastuximab talirine (33A) is a potent, highly stable antibody-drug conjugate composed of a humanized CD33-directed antibody conjugated at engineered cysteine residues to 2 molecules of pyrrolobenzodiazepine (PBD) via protease cleavable linkers. Upon binding to CD33, 33A is internalized and PBD is released leading to DNA cross-linking and cell death. RO on targeted cells following treatment administration is a pharmacodynamic measure of myeloblast exposure to 33A. Methods A phase 1 study (NCT01902329) assessed the safety and antileukemic activity of 33A as monotherapy. Best response was evaluated as CRc (CR + CR with incomplete count recovery), morphologic leukemia-free state, or resistant disease. Peripheral blood and bone marrow (BM) aspirates were collected for pharmacokinetic (PK) and biomarker analysis, including assessment of minimal residual disease negative (MRDneg) remission by 10-color flow cytometry. Calculated 33A PK parameters included the observed maximum concentration (Cmax) and the area under the concentration-time curve to the last quantifiable value (AUClast). Myeloblast CD33 levels were measured by multi-color flow cytometry using 2fluorophore conjugated anti-CD33 reagents (1 competitive with 33A). To assess RO, the relative fluorescence values for each reagent were compared in samples drawn before and 2 hours after IV 33A administration. RO was obtained from 71 evaluable patients; 57 (80%) had relapsed/refractory disease (median age 72); 14 patients were treatment naïve (median age 76). Results Cmax and AUClast increased with increasing dose. Dose-normalized (DN) AUClast declined with increasing baseline BM cellularity and myeloblast percentage. Greater RO was associated with greater Cmax and AUClast. In a univariate analysis, variables associated with odds of CRc included treatment naivety, DN Cmax, and AUClast. Variables associated with odds of MRDneg included RO, DN Cmax, Cmax and AUClast. RO ranged from <10% to >80%; across RO tertiles (32%, 55%), the odds of MRDneg remission increased from 4% (1/23) to 25% (6/24) to 50% (12/24). After accounting for dose, baseline BM myeloblasts, treatment naivety, and NPM1 mutation, the odds of CRc associated with DN Cmax and cytogenetic risk by MRC, while the odds of MRDneg associated with DN Cmax, Cmax, RO, and DN AUClast. Conclusions Dose normalized serum exposure to 33A declined with increased disease burden, as assessed by BM cellularity and myeloblasts. Exposure-related RO on peripheral blood myeloblasts confirmed CD33 targeting by 33A in patients. Together, these results support target-mediated disposition of 33A. An association of the odds of achieving MRDneg with RO, Cmax, and AUClast was observed with 33A monotherapy treatment. High RO was not required for patients to achieve CRc or MRDneg remission. Further efforts are underway to better understand the pharmacologic and molecular drivers of the deep, MRDneg remissions mediated by 33A. Citation Format: Charles Biddle-Snead, Jenna L. Voellinger, Phoenix Ho. Assessment of myeloblast CD33 receptor occupancy (RO) by vadastuximab talirine in patients with acute myeloid leukemia (AML) receiving monotherapy treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT120. doi:10.1158/1538-7445.AM2017-CT120

CASCADE: A phase 3, randomized, double-blind study of vadastuximab talirine (33A) versus placebo in combination with azacitidine or decitabine in the treatment of older patients with newly diagnosed acute myeloid leukemia (AML).

TPS7066 Background: AML is associated with poor survival rates in patients (pts) who are not eligible for intensive chemotherapy or allogeneic stem cell transplant (allo-SCT) due to advanced age, comorbidities, and/or disease risk factors. Non-intensive therapies, such as the hypomethylating agents (HMAs) azacitidine and decitabine, are frequently employed in this setting; however, response rates and survival remain suboptimal in this pt population. Vadastuximab talirine (33A) is a CD33-directed antibody conjugated to pyrrolobenzodiazepine (PBD) dimers. Upon binding, 33A is internalized and transported to the lysosomes where PBD is released via proteolytic cleavage of the linker, leading to DNA crosslinking and cell death. In preclinical studies, HMA priming followed by 33A exposure upregulated CD33 expression, increased DNA incorporation of the PBD dimer, and enhanced cytotoxicity. In a phase 1 study, 33A plus HMA was generally well tolerated without a significant pattern of off-target toxicity. Activity of the combination was markedly improved compared to historical data of HMA monotherapy, with a high MRD-negative remission rate and activity maintained in the highest risk subgroups (Fathi et al, ASH 2016). Methods: This phase 3, randomized, double-blind, placebo-controlled global study was designed to compare overall survival between pts treated with 33A plus HMA vs. pts treated with placebo plus HMA (NCT02785900). Secondary endpoints include composite complete remission rate (CR/CRi), event-free survival, and safety. Approximately 500 pts will be randomized in a 1:1 manner to one of the study arms. Investigators may select either HMA (azacitidine or decitabine). Eligible pts are adults with newly diagnosed, previously untreated, de novo or secondary AML, and have intermediate or adverse cytogenetic risk. Pts must not have AML associated with favorable risk karyotype or be a candidate for allo-SCT. Combination treatment may be repeated every 4 weeks until disease progression, leukemic recurrence, or unacceptable toxicity. Study enrollment began in June 2016.

What are the latest advancements in acute myeloid leukemia therapy?

What are the latest advancements in acute myeloid leukemia therapy?

Vadastuximab Talirine Plus Hypomethylating Agents: A Well-Tolerated Regimen with High Remission Rate in Frontline Older Patients with Acute Myeloid Leukemia (AML)

Vadastuximab Talirine Plus Hypomethylating Agents: A Well-Tolerated Regimen with High Remission Rate in Frontline Older Patients with Acute Myeloid Leukemia (AML)

A Phase 1b Study of Vadastuximab Talirine As Maintenance and in Combination with Standard Consolidation for Patients with Acute Myeloid Leukemia (AML)

A Phase 1b Study of Vadastuximab Talirine As Maintenance and in Combination with Standard Consolidation for Patients with Acute Myeloid Leukemia (AML)

Vadastuximab Talirine Monotherapy in Older Patients with Treatment Naive CD33-Positive Acute Myeloid Leukemia (AML)

BackgroundCD33is expressed in approximately 90% of AML cases, representing a promising target despite age, prior therapies, or mutational heterogeneity. Vadastuximab talirine (33A) is a CD33-directed antibody conjugated to 2 molecules of a pyrrolobenzodiazepine (PBD) dimer. Upon binding, 33A is internalized and transported to the lysosomes where PBD dimer is released via proteolytic cleavage of the linker, crosslinking DNA, and leading to cell death.MethodsThe dose-escalation portion of this phase 1 study (NCT01902329) was designed to evaluate the safety, tolerability, pharmacokinetics, and antileukemic activity of 33A as monotherapy. After dose escalation, 40 mcg/kg was identified as the recommended monotherapy dose. Eligible patients (ECOG status 0-1) in this expansion cohort must have had CD33-positive AML and considered ineligible for or declined conventional induction/consolidation. 33A monotherapy was administered outpatient IV every 3 weeks for up to 2 cycles, followed by optional low-dose maintenance treatment for patients who achieved a CR/CRi. Investigator assessment of response was per IWG criteria; CRi required either platelet count of ≥100,000/µL or neutrophils of ≥1,000/µL (Cheson 2003).ResultsTwenty-seven treatment naive patients (48% male) with a median age of 74 years (range, 67-89) were treated with 40 mcg/kg of 33A. Most patients had intermediate (70%) or adverse (26%) cytogenetic risk by MRC and 48% of patients had underlying myelodysplasia. Twenty-four patients were considered unfit for intensive therapy and 3 patients declined intensive therapy. At baseline, patients had a median of 47% BM blasts. Three patients remain on treatment. The most common Grade 3 or higher adverse events (AE) were thrombocytopenia (44%), febrile neutropenia (41%), anemia (33%), fatigue, and pneumonia (19% each). Other common treatment-emergent AEs regardless of relationship to 33A were decreased appetite, diarrhea, fatigue, peripheral edema, thrombocytopenia (44% each), febrile neutropenia (41%), dizziness (37%), anemia, chills, cough, dyspnea, and epistaxis (33% each). The 30- and 60-day mortality rates were 0% and 15%. Of the 26 efficacy evaluable treatment naive patients, 6 patients (23%) achieved a best clinical response of CR, 8 (31%) achieved CRi, and 5 patients (19%) achieved a morphologic leukemia-free state. Most remissions were achieved after 1 cycle and were observed in many patients with adverse risk including underlying myelodysplasia (6/12, 50%), FLT3/ITD+ (3/4, 75%), and in patients ≥75 years of age (8/12, 67%). Of the responding patients with available minimal residual disease (MRD) data, 6 of 13 (46%) achieved MRD negativity by flow cytometry. In patients who achieved at least a CRi, the median time to full count recovery from first dose was 6.1 weeks for neutrophils (≥1,000/µL) and 5.1 weeks for platelets (≥100,000/µL). Median OS continues to evolve with 10 patients (37%) alive at the time of this data cut. Pharmacokinetic data for treatment naive patients is consistent with previously reported results; 33A exhibits rapid elimination consistent with target-mediated drug disposition.ConclusionsIn an expansion cohort of 33A monotherapy at 40 mcg/kg, AEs observed were generally manageable and commonly associated with on-target myelosuppression. 33A has demonstrated favorable antileukemic activity as a single agent with 54% achieving a CR+CRi in this high risk treatment naive older AML population, more than doubling the response rate expected with standard non-intensive therapies such as hypomethylating agents or low-dose cytarabine. The rapid clearance of marrow blasts, high rate of MRD-negative remissions, and low early mortality rate are encouraging. These data support exploration of 33A in combination with standard induction, consolidation, and pre- and post-transplant regimens. DisclosuresStein:Celgene: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Research Funding. Fathi:Agios Pharmaceuticals: Other: Advisory Board participation; Bexalata: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Celgene: Consultancy, Research Funding; Merck: Other: Advisory Board participation. Kovacsovics:Seattle Genetics: Research Funding. Levy:Seattle Genetics: Research Funding; Jansen: Speakers Bureau; Amgen: Speakers Bureau; Millennium: Speakers Bureau. Erba:Daiichi Sankyo: Consultancy; Jannsen: Consultancy, Research Funding; Celator: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Juno: Research Funding; Astellas: Research Funding; Ariad: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Pfizer: Consultancy; Agios: Research Funding; Novartis: Consultancy, Speakers Bureau; Gylcomimetics: Other: DSMB; Seattle Genetics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Sunesis: Consultancy. Jillella:Seattle Genetics: Research Funding. Ravandi:Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Stein:Novartis: Consultancy; Seattle Genetics: Research Funding; Agios Pharmaceuticals: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding. Faderl:Astellas: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Celator Pharmaceuticals: Research Funding; BMS: Research Funding; Ambit Bioscience: Research Funding; Karyopharm: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; JW Pharma: Consultancy; Amgen: Speakers Bureau. DeAngelo:Baxter: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Incyte: Consultancy; Pfizer: Consultancy; Ariad: Consultancy; Celgene: Consultancy. Ho:Seattle Genetics: Employment, Equity Ownership. O'Meara:Seattle Genetics: Employment, Equity Ownership. Voellinger:Seattle Genetics: Employment, Equity Ownership. Advani:Seattle Genetics: Consultancy, Research Funding.

A Phase 1b Study of Vadastuximab Talirine in Combination with 7+3 Induction Therapy for Patients with Newly Diagnosed Acute Myeloid Leukemia (AML)

A Phase 1b Study of Vadastuximab Talirine in Combination with 7+3 Induction Therapy for Patients with Newly Diagnosed Acute Myeloid Leukemia (AML)

ADCs Show Promise in Leukemias.

According to a phase III study, the antibody-drug conjugate inotuzumab ozogamicin is more likely to induce complete remissions, with full or incomplete hematologic recovery, in patients with relapsed or refractory acute lymphocytic leukemia. Data from a phase I study of another antibody-drug conjugate, vadastuximab talirine, demonstrates that it is safe and effective against acute myeloid leukemia.

Abstract 4778: Covalent bonding of a C8-conjugated pyrrolobenzodiazepine (PBD) monomer and dimer to a terminal guanine residue of DNA duplex and hairpin fragments

Abstract The pyrrolobenzodiazepines (PBDs) are a family of covalent-binding DNA-interactive minor-groove binding agents that are of growing interest due to their potential as stand-alone anticancer agents, and for their use as payloads in Antibody Drug Conjugates (ADCs). For example, one PBD Dimer, SJG-136 has reached Phase II evaluation in the clinic for ovarian and haematological cancers, and a number of PBD-based ADCs are now being evaluated in pre-clinical, Phase I and II clinical trials (e.g., SGN-CD19B, SGN-CD33A [vadastuximab talirine], SGN-CD70A, SGN-CD123A, SC16LD6.5 [Rova-T, rovalpituzumab tesirine] and ADCT-402). Until now, PBDs, which bind in the minor groove of DNA and covalently bond to a guanine residue through its C2-NH2 functional group, were thought to require a three-base-pair recognition sequence prior to covalent bonding to the central guanine (with a thermodynamic preference for binding to 5’-Pu-G-Pu-3’ sequences but a kinetic preference for 5’-Py-G-Py-3’; Pu = Purine, Py = Pyrimidine). Using HPLC/MS methodology with designed hairpin and duplex oligonucleotides, we have now demonstrated that the PBD dimer SJG-136 and the C8-conjugated PBD Monomer GWL-78 can covalently bond to a terminal guanine of DNA, with the PBD skeleton spanning only two base pairs. Control experiments with the non-C8-conjugated anthramycin along with molecular dynamics simulations suggest that the C8-substituent of a PBD monomer, or one-half of a PBD Dimer, may provide stability for the adduct. This observation highlights the importance of PBD C8-substituents, and also suggests that PBDs may bind to terminal guanines within stretches of DNA in cells, thus representing a potentially novel mechanism of action at the end of DNA strand breaks. Citation Format: Julia Mantaj, Paul J. M. Jackson, Khondaker Miraz Jackson, David E. Thurston. Covalent bonding of a C8-conjugated pyrrolobenzodiazepine (PBD) monomer and dimer to a terminal guanine residue of DNA duplex and hairpin fragments. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4778.

SGN-CD33A (Vadastuximab Talirine) followed by Allogeneic Hematopoietic Stem Cell Transplant (AlloHSCT) Results in Durable Complete Remissions (CRs) in Patients with Acute Myeloid Leukemia (AML)

SGN-CD33A (Vadastuximab Talirine) followed by Allogeneic Hematopoietic Stem Cell Transplant (AlloHSCT) Results in Durable Complete Remissions (CRs) in Patients with Acute Myeloid Leukemia (AML)

Abstract DDT01-04: SGN-CD19A: A novel Anti-CD19 antibody drug conjugate

Abstract CD19, a member of the immunoglobulin superfamily, is a B-cell specific marker that is found on B cells as early as the pro-B cell stage. CD19 is maintained upon malignant transformation and is expressed in the majority of patients with B-lineage acute lymphocytic leukemia (ALL) and non-Hodgkin lymphoma (NHL). SGN CD19A is a novel antibody-drug conjugate (ADC) composed of a humanized anti-CD19 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF) via a maleimidocaproyl (mc) linker. Upon binding to CD19, SGN-CD19A internalizes and releases cys-mcMMAF, which binds to tubulin and induces G2/M arrest and apoptosis in the targeted cells. In mice bearing B-lineage ALL and lymphoma xenografts, SGN-CD19A induced dose-dependent tumor growth delay and extended survival. Two first-in-human, phase 1, dose-escalation studies are ongoing to investigate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of SGN CD19A; one trial in adult and pediatric patients with relapsed or refractory (R/R) B cell ALL or highly aggressive B-cell lymphoma (CT.gov NCT01786096) and the second trial in adult patients with R/R B-cell NHL (CT.gov NCT01786135). Both trials employ a modified continual reassessment method (CRM) to estimate the dose-toxicity relationship and to estimate the maximum tolerated dose. Exploratory analyses include correlation of target (CD19) expression, target saturation, and apoptotic cellular markers with clinical response and clearance of leukemic blasts; dose and PK of SGN-CD19A will also be correlated with target saturation and intracellular levels of cys-mcMMAF. Early PK analyses indicate that plasma SGN-CD19A ADC generally increases with higher doses. Rapid clearance of ADC was observed at low doses in patients with leukemia, suggesting target-mediated drug disposition. Dose escalation of SGN-CD19A is ongoing in both clinical trials. In preliminary safety analyses, SGN-CD19A was generally tolerable at doses examined to date. Encouraging antitumor activity has been observed, with multiple patients achieving complete remissions in both trials. Citation Format: Tina M. Albertson, Lali Sandalic, Baiteng Zhao, Ana Kostic, Che-Leung Law. SGN-CD19A: A novel Anti-CD19 antibody drug conjugate. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr DDT01-04. doi:10.1158/1538-7445.AM2014-DDT01-04