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

Stein, Eytan M.; Walter, Roland B.; Erba, Harry P.; Fathi, Amir T.; Advani, Anjali S.; Lancet, Jeffrey E.; Ravandi, Farhad; Kovacsovics, Tibor; DeAngelo, Daniel J.; Bixby, Dale; Faderl, Stefan; Jillella, Anand; Ho, Phoenix A.; O’Meara, Megan M.; Zhao, Bin; Biddle-Snead, Charles; Stein, Anthony S.

doi:10.1182/blood-2017-06-789800

Cited by 151 publications

(98 citation statements)

References 14 publications

(12 reference statements)

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“…In the phase 1 dose escalation study of SGN-CD33A, the most common grade 3 adverse events were febrile neutropenia, thrombocytopenia, and anemia. 41 These adverse events are consistent with on-target myelosuppression because of CD33 expression on myeloid progenitors. Although nontargeted myelosuppression is possible with ADCs, we anticipate a lesser degree of myelosuppression with SGN-CD19B relative to SGN-CD33A because of the fact that CD19 expression is restricted to the B-cell lineage.…”

Section: Discussionsupporting

confidence: 62%

“…These data compare favorably to preclinical data shown for INO, 53 which recently met its clinical end point in a pivotal phase 3 randomized trial in relapsed/refractory B-ALL demonstrating a significantly higher rate of complete response compared with standard chemotherapy (80.7% vs 29.4%, P , .001). 54 The accessibility of leukemic blasts and confirmed antileukemic activity seen with DNA alkylating agents, including PBD ADCs, 55 suggest that SGN-CD19B may have a high probability of technical success in B-ALL.…”

Section: Discussionmentioning

confidence: 95%

“…40 The distinct mechanism and properties of PBD dimers appear to confer activity in multidrug resistant (MDR1) tumor cells. For instance, preclinical studies on SGN-CD33A, a CD33-directed ADC studied in myeloid malignancies, 41 revealed activity against MDR1 primary acute myeloid leukemia tumor samples.…”

Section: Discussionmentioning

confidence: 99%

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Therapeutic potential of SGN-CD19B, a PBD-based anti-CD19 drug conjugate, for treatment of B-cell malignancies

Ryan¹,

Palanca-Wessels

Schimpf³

et al. 2017

Blood

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• SGN-CD19B is broadly active in vitro against malignant B-cell lines, including doublehit and triple-hit lymphoma cell lines.• SGN-CD19B shows significant antitumor activity in vivo in preclinical models of B-NHL and B-cell-derived acute lymphoblastic leukemia.Patients with relapsed/refractory B-cell malignancies such as non-Hodgkin lymphoma (B-NHL) or acute lymphoblastic leukemia have a poor prognosis. Despite measurable clinical activity with new targeted therapies, many patients do not achieve a complete or durable response suggesting an opportunity to improve upon existing therapies. Here we describe SGN-CD19B, a pyrrolobenzodiazepine (PBD)-based anti-CD19 antibody drug conjugate (ADC) being investigated for treatment of B-cell malignancies, which has improved potency compared with other ADCs. CD19-expressing tumor cells rapidly internalize SGN-CD19B, and the released PBD drug induces DNA damage, resulting in G2/M cell cycle arrest and cell death. SGN-CD19B demonstrated activity against a broad panel of malignant B-cell lines and induced durable regressions in mice bearing xenografts derived from these B-cell malignancies. A single dose of SGN-CD19B induced durable regressions at 300 mg/kg (3 mg/kg drug equivalents); combination with rituximab decreased the curative dose to 100 mg/kg (1 mg/kg drug equivalents). These doses are significantly lower than the level of drug required with other ADC payloads. In cynomolgus monkeys, SGN-CD19B effectively depleted CD20 1 B lymphocytes in peripheral blood and lymphoid tissues confirming that SGN-CD19B is pharmacodynamically active at well-tolerated doses. In summary, preclinical studies show SGN-CD19B is a highly active ADC, which releases a DNA cross-linking agent rather than a microtubule inhibitor. The distinct mechanism of action, broad potency, and potential to combine with rituximab suggest that SGN-CD19B may offer unique clinical opportunities in B-cell malignancies. A phase 1 clinical trial is in progress to investigate the therapeutic potential of SGN-CD19B in relapsed/refractory B-NHL.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 95%

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Therapeutic potential of SGN-CD19B, a PBD-based anti-CD19 drug conjugate, for treatment of B-cell malignancies

Ryan¹,

Palanca-Wessels

Schimpf³

et al. 2017

Blood

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“…These doses were chosen to result in approximately 10%, 50% and 90% RO at C max to explore a full range of predictions from the model and to include doses comparable to first-in-human doses administered in the clinic for other ADCs bearing pyrrolobenzodiazepine (PBD, a DNA binding agent) payloads. 37-39 To evaluate the impact of the uncertainty of the parameters characterizing the PK nonlinearity on the human PK and RO predictions, we generated a multivariate normal distribution of 1000 pairs of values for V max and log(KM) using the model estimations and their covariance matrix. The predicted C max values for these simulated doses were 6.81, 65.4 and 572 ng/mL, respectively.…”

Section: Resultsmentioning

confidence: 99%

Prediction of non-linear pharmacokinetics in humans of an antibody-drug conjugate (ADC) when evaluation of higher doses in animals is limited by tolerability: Case study with an anti-CD33 ADC

Figueroa

Leipold

Leong

et al. 2018

mAbs

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For antibody-drug conjugates (ADCs) that carry a cytotoxic drug, doses that can be administered in preclinical studies are typically limited by tolerability, leading to a narrow dose range that can be tested. For molecules with non-linear pharmacokinetics (PK), this limited dose range may be insufficient to fully characterize the PK of the ADC and limits translation to humans. Mathematical PK models are frequently used for molecule selection during preclinical drug development and for translational predictions to guide clinical study design. Here, we present a practical approach that uses limited PK and receptor occupancy (RO) data of the corresponding unconjugated antibody to predict ADC PK when conjugation does not alter the non-specific clearance or the antibody-target interaction. We used a 2-compartment model incorporating non-specific and specific (target mediated) clearances, where the latter is a function of RO, to describe the PK of anti-CD33 ADC with dose-limiting neutropenia in cynomolgus monkeys. We tested our model by comparing PK predictions based on the unconjugated antibody to observed ADC PK data that was not utilized for model development. Prospective prediction of human PK was performed by incorporating in vitro binding affinity differences between species for varying levels of CD33 target expression. Additionally, this approach was used to predict human PK of other previously tested anti-CD33 molecules with published clinical data. The findings showed that, for a cytotoxic ADC with non-linear PK and limited preclinical PK data, incorporating RO in the PK model and using data from the corresponding unconjugated antibody at higher doses allowed the identification of parameters to characterize monkey PK and enabled human PK predictions.

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“…Measuring payload may prove challenging with the development of more potent payloads; next-generation chemotypes such as pyrrolobenzodiazepine dimers have activity at subpicomolar concentrations, 84 with ADC doses in the microgram per kilogram range. 85 Similarly, our understanding of ADC immunogenicity is limited by assay limitations, with interpretations affected by assay sensitivity and specificity, drug interference, and sample handling and timing. Although data suggest little impact of immunogenicity on ADC function, variations in current assay methods, along with confounding factors such as the underlying disease, patient immunological status, and the general paucity of data make it difficult to draw firm conclusions.…”

Section: Areas For Further Discussion and Considerationmentioning

confidence: 99%

Antibody–Drug Conjugates as Cancer Therapeutics: Past, Present, and Future

Vezina

Cotreau

Han

et al. 2017

The Journal of Clinical Pharma

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Antibody-drug conjugates (ADCs) represent an innovative therapeutic approach that provides novel treatment options and hope for patients with cancer. By coupling monoclonal antibodies (mAbs) to cytotoxic small-molecule payloads with a plasma-stable linker, ADCs offer the potential for increased drug specificity and fewer off-target effects than systemic chemotherapy. As evidence for the potential of these therapies, many new ADCs are in various stages of clinical development. Because their structure poses unique challenges to pharmacokinetic and pharmacodynamic characterization, it is critical to recognize the differences between ADCs and conventional chemotherapy in the design of ADC clinical development strategies. Although some properties may be determined mainly by either the mAb or the small-molecule portion, the behavior of these agents is not always predictable. Furthermore, because the absorption, distribution, metabolism, and excretion (ADME) of ADCs are influenced by all 3 of its components (mAb, linker, and payload), it is important to characterize the intact molecule, any target-mediated catabolic clearance of the mAb, and the ADME properties of the small-molecule payload. Here we describe key issues in the clinical development of ADCs, including considerations for designing first-in-human studies for ADCs. We discuss some difficulties of ADC pharmacokinetic characterization and current approaches to overcoming these challenges. Finally, we consider all aspects of clinical pharmacology assessment required during drug development, using examples from the literature to illustrate the discussion.

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

Cited by 151 publications

References 14 publications

Therapeutic potential of SGN-CD19B, a PBD-based anti-CD19 drug conjugate, for treatment of B-cell malignancies

Therapeutic potential of SGN-CD19B, a PBD-based anti-CD19 drug conjugate, for treatment of B-cell malignancies

Prediction of non-linear pharmacokinetics in humans of an antibody-drug conjugate (ADC) when evaluation of higher doses in animals is limited by tolerability: Case study with an anti-CD33 ADC

Antibody–Drug Conjugates as Cancer Therapeutics: Past, Present, and Future

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