Abstract
On December 20, 2018, the Food and Drug Administration approved calaspargase pegol-mknl (CALASP), an asparagine-specific enzyme, as a component of a multi-agent chemotherapeutic regimen for acute lymphoblastic leukemia (ALL) in pediatric and young adult patients age 1 month to 21 years. Efficacy was determined on the basis of achievement and maintenance of steady-state nadir serum asparaginase activity (NSAA) above 0.1 U/mL when using CALASP, 2,500 U/m2 intravenously, every 3 weeks. In a randomized comparison to pegaspargase (PEGASP) every 2 weeks, treatment with CALASP every 3 weeks had a similar safety profile and no substantial impairment in event-free survival. The pharmacokinetics of CALASP were studied when administered in combination with multiagent chemotherapy in 124 patients with B-cell ALL in Study AALL07P4 and Study DFCI 11-001. The results showed that 123 [99%, 95% confidence interval (CI), 96%–100%] of the 124 patients maintained NSAA >0.1 U/mL at weeks 6, 12, 18, 24, and 30 of post-induction phase. Maintaining adequate NSAA levels is critical to successful treatment of ALL. Herein, we describe the FDA review and approval of CALASP.
See related commentary by Lew, p. 325
Introduction
More than 95% of children with newly diagnosed acute lymphoblastic leukemia (ALL) attain a complete remission (CR) after induction chemotherapy, and approximately 80% treated with multi-agent chemotherapy that includes asparaginase agents are expected to be long-term survivors. Asparaginase agents have been an important component of pediatric ALL therapy since the early 1970s. The incorporation of asparaginase agents as a component of therapy was shown to add a 15% to 20% survival benefit to children with ALL (1), and adherence to the planned dose-intensity was important for optimal survival outcome (2).
Calaspargase pegol-mknl (CALASP, Asparlas, Servier Pharmaceuticals LLC), a long-acting product, is a recombinant protein comprised of an E. coli L-asparaginase homotetramer and 31–39 molecules of monomethoxy-polyethylene glycol (mPEG) with a succinimidyl carbonate (SC) linker. Herein, we summarize the FDA review of the application of CALASP as a component of a multi-agent chemotherapeutic regimen for the treatment of ALL in pediatric and young adult patients age 1 month to 21 years.
Clinical Trials
Two clinical trials, Study AALL07P4 and Study DFCI 11-001, were considered in the review of this application. Study AALL07P4 was an open-label multicenter randomized trial comparing PEGASP 2,500 IU/m2, CALASP 2,100 U/m2 and CALASP 2,500 U/m2 in combination with chemotherapy for treatment of patients with high-risk ALL. Study DFCI 11-001 was an open-label multicenter randomized trial comparing PEGASP 2,500 IU/m2 and CALASP 2,500 U/m2 in combination with chemotherapy for treatment of patients with ALL or lymphoblastic lymphoma. Details of the chemotherapy used in each study are described elsewhere (3, 4). Figure 1 shows an overview of asparaginase product dosing during each phase of treatment in the protocols.
Overview of Asparaginase Product Administration in Study AALL07P4 and Study DFCI 11-001. A, In Study AALL07P4, the patients were randomized 2:1 to receive CALASP 2,500 U/m2 or PEGASP 2500 IU/m2 given on the days indicated (total 7–12 doses depending on response during induction). During the conduct of the study, the protocol was amended to reduce the planned dose of CALASP to 2,100 U/m2: The protocol was later re-amended to return to the original CALASP 2,500 U/m2 dose. aDose of calaspargase-mknl changed during the course of the protocol. bExtended induction (2 weeks) included CALASP or PEGASP on Day 4. cOnly for patients with slow early response. B, In Study DFCI 11-001, the patients were randomized 1:1 to receive CALASP or PEGASP 2,500 IU/m2 once during induction, once during CNS therapy, and every 3 weeks thereafter for CALASP (total 11 doses) or every 2 weeks thereafter for PEGASP (total 16 doses) through Consolidation II. In both studies, the asparaginase product was given in addition to multiagent chemotherapy (3, 4).
The asparaginase activity is the basis of pharmacokinetic (PK) assessment in the clinical pharmacology program of CALASP. For Study AALL07P4, blood for PK testing was collected during induction phase (Days 4, 5, 6, 8, 15, 22, and 29) and consolidation phase (Days 15, 16, 17, 22, 29, 36, and 43). For Study DFCI 11-001, PK samples were collected at 5 to 10 minutes, day 4, 11, 18 and 25 post-dose during induction phase. In post-induction phase, asparaginase activity was measured immediately before each dose as NSAA every 3 weeks (9 PK samples per subject were scheduled following the first post-induction dose). Plasma asparaginase activity was measured with a validated enzymatic coupled activity assay.
Clinical Effectiveness
The determination of efficacy was based on a demonstration of the achievement and maintenance of steady-state NSAA above the level of 0.1 U/mL using CALASP 2,500 U/m2 intravenously every 3 weeks. NSAA is considered an established surrogate PD endpoint for clinical efficacy of asparaginase treatment.
In Study DFCI 11-001, 237 patients were randomized and treated with either CALASP 2,500 IU/m2 (n = 118) or PEGASP 2,500 IU/m2 (n = 119). Although the exposure to asparaginase activity was a primary endpoint of the study, there were only 13 patients in the CALASP arm and only 16 patients in the PEGASP arm with evaluable PK samples. Because the low number of patients with evaluable observed PK data in Study DFCI 11-001 lacks power for any decision making, Study DFCI 11-001 was not sufficient on its own for the evaluation of NSAA for the determination of efficacy.
In Study AALL07P4, 163 patients were randomized and treated with CALASP 2,100 U/m2 (n = 68), CALASP 2,500 U/m2 (n = 43), or PEGASP 2,500 IU/m2 (n = 52). Evaluable PK samples were available for all treated patients, but because CALASP was given with different dosing intervals in Study AALL07P4, the observed NSAA levels were not directly evaluable for the evaluation of the proposed dosing every 3 weeks.
The review team used an imputation method based on the population PK (PPK) modeling and simulation and the limited observed PK data to evaluate NSAA for the proposed dosing regimen of CALASP 2,500 U/m2 every 3 weeks. All patients from Studies AALL07P4 and DFCI 11-001 with at least one valid PK observation were included in the imputation. Specifically, the PPK model originally developed by the applicant was updated on the basis of the valid PK data from 124 subjects (13 from Study DFCI 11-001 and 111 from Study AALL07P4). Demographics of the PK population are listed in Table 1.
Baseline characteristics of the PK and safety populations.
The individual PK parameters of each subject were estimated by the updated population PK model. The asparaginase activity of the subject PK at any time point, including NSAA at steady-state, under the proposed dosing regimen of 2,500 U/m2 every 3 weeks could then be imputed. Imputation data showed that 99% [95% confidence interval (CI), 96%–100%]) of the subjects (123 out of 124) would maintain NSAA ≥0.1 U/mL from Week 6 to Week 30 during the post-induction phase with CALASP given the proposed dose regimen of 2,500 U/m2 every 3 weeks.
As supportive evidence of effectiveness, depletion of plasma and cerebrospinal fluid (CSF) asparagine concentrations following the single induction dose and the first consolidation dose were assessed in Study AALL07P4. During the induction phase, plasma asparagine concentrations were rapidly depleted to below the assay lower limit of quantitation (LLOQ, 0.05 μg/mL) at 5 minutes post dose regardless of treatment groups and remained below the LLOQ for the entire sampling duration up to 25 days post dose. Similarly, the median plasma asparagine concentrations were below the LLOQ for all three treatment groups following the first dose in the consolidation phase at all PK sampling timepoints. CSF asparagine concentrations were suppressed to near or below the LLOQ after the single induction dose and the first consolidation dose regardless of treatment groups. In summary, CALASP treatment suppresses plasma and CSF asparagine concentrations to a similar extent as PEGASP.
Clinical Safety
The safety of CALASP 2,500 U/m2 given no more frequently than every 3 weeks was investigated in Study DFCI 11-001. The baseline characteristics of the 237 patients in the safety population are listed in Table 1. The median number of doses during the study was 11 doses for CALASP (administered every 3 weeks) and 16 doses for PEGASP (administered every 2 weeks). The median duration of exposure was 8 months for both CALASP and PEGASP.
There was 1 fatal adverse reaction (multi-organ failure in the setting of chronic pancreatitis associated with a pancreatic pseudocyst) in a patient treated with CALASP. Discontinuations were slightly higher on the CALASP arm (33% vs. 24%), and the most common reasons for discontinuation were allergic reactions (15% vs. 13%) and pancreatitis (13% vs. 11%). The incidence of selected grades ≥3 adverse reactions are shown in Table 2. Because not all grade 1 and 2 adverse reactions were collected prospectively, only grades ≥3 adverse reactions are shown. There were no substantial differences between the treatment arms for grades ≥3 adverse reactions. Adverse reactions by treatment phase are listed in Supplementary Table S2.
Selected grades ≥ 3 adverse reactions in study DFCI 11-001.
Study DFCI 11-001 was not designed to assess effectiveness on the basis of a clinical outcome, but any obvious decrement in measures of effectiveness would be considered a potential safety disadvantage. In the subgroup of patients with Philadelphia-negative B-cell lineage ALL in Study DFCI 11-001, a remission with a documented M1 marrow was reported in 94/97 (97%) in the CALASP arm and 94/99 (95%) in the PEGASP arm. There was no grossly discernable difference between the treatment arms for Kaplan–Meier estimates of overall survival.
Regulatory Insights
Although FDA usually requires a demonstration of direct clinical benefit for approval of new drugs, achievement and maintenance of NSAA ≥0.1 U/mL correlates with depletion of CSF and serum asparagine (5–7) and has been used as an established surrogate of effectiveness for asparaginase class products in combination with chemotherapy for first-line treatment of ALL (Oncaspar PI, Erwinaze PI). The pharmacometrics analysis of CALASP showed that 123 (99%; 95% CI, 96%–100%) of the 124 patients would maintain NSAA ≥0.1 U/mL at weeks 6, 12, 18, 24, and 30 when dosed every 3 weeks. The high rate of durable success (99%) with the high level of confidence (lower 95% CI bound 96%) was considered substantial evidence of effectiveness.
It should be noted that there is no established biomarker for safety of asparaginase class products. The comparative clinical safety data from Study DFCI 11-001 was key to the risk-benefit analysis of CALASP for this approval. The safety analysis showed no substantial differences between CALASP given every 3 weeks and PEGASP given every 2 weeks for the safety profile. The incidence of hypersensitivity reactions and discontinuations due to allergic reaction were also similar between arms. A comparison of the rates of antidrug antibody (ADA) formation could not be performed, since data were not available for review. Given the importance of ADA to hypersensitivity reactions, silent inactivation, and loss of effectiveness, the sponsor committed to further study of ADA under the conditions of this approval.
On the basis of the mechanism of action of CALASP and the biology of ALL across age groups, one might conclude that CALASP would be effective in combination regimens regardless of age and consider extrapolating efficacy to a population older than that accrued to the supporting clinical trials. However, current data from other asparaginase class products suggest that the limits of safe dosing might vary with age (8). Consequently, in the absence of safety data in the older population, the approved indication is limited to patients up to 21 years old.
Finally, it should be noted that the recommended dosage of CALASP pertains to the solely to CALASP alone and not to the other drugs used in the multi-agent chemotherapy regimens. The safety profile displayed in labeling is based only on CALASP in combination with the Dana Farber Cancer Institute (DFCI) ALL Consortium backbone therapy. In fact, labeling also highlights the increased induction mortality when used in combination with the augmented Berlin-Frankfurt-Münster (BFM) therapy regimen, albeit in a different schedule. Development of combinations of CALASP with other regimens should proceed using standard approaches to ensure safety of the new combination before commencing large studies or generalized use.
In conclusion, the pharmacometrics analysis for CALASP and the comparative safety data from DFCI 11-001 supported regular approval of CALASP as a component of a multi-agent chemotherapeutic regimen for the treatment of ALL in pediatric and young adult patients age 1 month to 21 years using a dose of 2,500 U/m2 given no more frequently than every 3 weeks.
Disclosure of Potential Conflicts of Interest
A. Deisseroth is an unpaid consultant/advisory board member for MicroVAX LLC and VAXum LLC. No potential conflicts of interest were disclosed by the other authors.
Disclaimer
The Editor handling the peer review and decision-making process for this article has no relevant employment associations to disclose. This is a U.S. Government work. There are no restrictions on its use.
Authors' Contributions
Conception and design: C. Liu, X. Cao, D. Przepiorka, K.B. Goldberg, R. Pazdur
Development of methodology: R.-J. Li, C. Liu, D. Przepiorka, R. Pazdur
Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): R. Pazdur
Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): R.-J. Li, R. Jin, C. Liu, X. Cao, D. Przepiorka, R. Pazdur
Writing, review, and/or revision of the manuscript: R.-J. Li, R. Jin, C. Liu, X. Cao, M.L. Manning, D. Przepiorka, F. Namuswe, K.B. Goldberg, G.M. Blumenthal, R. Pazdur
Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): R.-J. Li, R. Jin, X.M. Di, D. Przepiorka, A. Deisseroth, K.B. Goldberg, G.M. Blumenthal, R. Pazdur
Study supervision: C. Liu, D. Przepiorka, R. Pazdur
Footnotes
Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
Clin Cancer Res 2020;26:328–31
- Received April 19, 2019.
- Revision received June 6, 2019.
- Accepted August 21, 2019.
- Published first August 23, 2019.
- ©2019 American Association for Cancer Research.
Volume 26, Issue 2
